A drug-drug interaction (DDI) is a pharmacokinetic or pharmacological influence of 1 medication on another that differs from the known or anticipated effects of each agent alone.1 A DDI may result in a change in either drug efficacy or
drug toxicity for 1 or both of the interacting medications.2 Pharmacokinetic DDIs result in altered absorption, distribution, metabolism, or excretion of a medication. A pharmacodynamic DDI occurs when 1 medication modifies the pharmacological effect of another in an additive, a synergistic, or an antagonistic fashion.
It is estimated that ≈2.8% of hospital admissions occur as a direct result of DDIs.3 However, the actual incidence of hospitalization secondary to clinically significant DDIs is likely to be highly underestimated because medication-related issues are more commonly reported as adverse drug reactions. Complex underlying disease states also may make recognizing a DDI more challenging, further contributing to a lower reported incidence. The overall clinical impact of a DDI can range from mild to life-threatening. Therefore, not all DDIs require a modification in therapy. The vari-ability in the clinical significance of a DDI depends on both medication-specific and patient-specific factors. Medication-specific factors include the individual pharmaco-kinetic characteristics of each medication implicated in the DDI (eg, binding affinity, half-life [t1/2]), dose of the medications, serum concentrations, timing and sequence of administration, and duration of therapy. Patient-specific factors include age, sex, lifestyle, genetic polymorphisms causing differences in enzyme expression or activ-ity, and disease impairment affecting drug metabolism (eg, hepatic or renal impair-ment, cardiac failure) or predisposition to differences in efficacy or safety (eg, statin intolerance in patients with a history of myopathy).
Clinically significant DDIs are usually preventable. To optimize patient safety, healthcare providers must have an understanding of the mechanisms, magnitude, and potential consequences of any given DDI. Interpreting this information will assist clinicians in the safe prescribing of medications and permits careful consideration of the benefits and risks of concomitant medications.
Statins reduce morbidity and mortality in patients with known atherosclerotic car-diovascular disease (ASCVD) and in many primary prevention patients.4–9 Current guidelines recommend high-intensity statin therapy in all patients with ASCVD age ≤75 years and moderate- to high-intensity statin therapy in patients with ASCVD and age >75 years, diabetes mellitus, and familial hypercholesterolemia and in primary prevention patients with 10-year ASCVD risk ≥7.5%.10 Given the important role of statins in patients with ASCVD and those at high ASCVD risk, combination therapy with statins and other cardiovascular medications is highly likely, and potentially significant DDIs must be considered in patients treated with statins.
Another important aspect of prescribing medications in combination is evaluating the risks versus benefits. Given the continuing increase in healthcare costs, trying to minimize costs to the health system through minimization of adverse effects and optimizing efficacy is of paramount importance. Prescription drug coverage and
Barbara S. Wiggins, PharmD, FAHA, Chair
Joseph J. Saseen, PharmD, FAHA, Co-Chair
Robert L. Page II, PharmD, MSPH, FAHA
Brent N. Reed, PharmD, FAHA
Kevin Sneed, PharmDJohn B. Kostis, MD, FAHADavid Lanfear, MD, FAHASalim Virani, MDPamela B. Morris, MD, FAHAOn behalf of the American
Heart Association Clini-cal Pharmacology Com-mittee of the Council on Clinical Cardiology; Council on Hyperten-sion; Council on Quality of Care and Outcomes Research; and Council on Functional Genom-ics and Translational Biology
Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular DiseaseA Scientific Statement From the American Heart Association
affordability may often dictate which medications may be prescribed. Patients who have exhausted prescrip-tion drug coverage or who are uninsured may require less-than-ideal medication combinations to provide the most cost-effective strategy possible. Therefore, a clear understanding of the magnitude and clinical significance of DDIs will enable clinicians to make well-informed de-cisions to provide evidence-based and cost-effective health care as safely as possible.
This document reviews the basics of DDIs, the phar-macological differences in the various statins, and the significance of statin DDIs with select medications used to treat patients with cardiovascular disease. Recom-mendations on the clinical management of these DDIs are provided to enable clinicians to optimize manage-ment while minimizing untoward effects. The writing committee considered data from clinical trials, case reports, prescribing information, and pharmacokinetic studies to provide guidance on how statin DDIs with se-lect medications used in cardiovascular patients should be managed. A summary of the evidence and the spe-cific recommendations for the clinical management of the DDIs discussed are given in Tables 1 and 2.
OvERvIEW OF DDIs, CyTOCHROME P-450 ENzyMES, AND PERMEAbILITy GLyCOPROTEINThe 2 most common pharmacokinetic DDIs involving statins are those mediated by the cytochrome P-450 (CYP450) enzyme system and permeability glycoprotein (P-gp). Pharmacodynamic DDIs with statins may also oc-cur. All DDIs can result in altered low-density lipoprotein cholesterol reductions or an enhanced risk of muscle-related toxicity.
DDIs Involving the CyP450 Enzyme SystemThe CYP450 gene superfamily encodes a series of oxi-dative enzymes involved in the biosynthesis of several physiologically important compounds (eg, steroids and fatty acids) and the metabolism of drugs and other exog-enous chemical products.11,12 In CYP450 nomenclature, enzymes sharing ≥40% similarity are categorized into families designated by an Arabic numeral (eg, CYP2 fam-ily) and those sharing ≥55% similarity are further classi-fied into subfamilies designated by a letter (eg, CYP2C subfamily).11 Within each subfamily, individual enzymes responsible for a unique metabolic route are numbered (eg, CYP2C19 enzyme). For those enzymes associated with genetic polymorphisms that encode allelic variants, an asterisk followed by a number (and in some cases an additional letter) may also be used (eg, CYP2C19*2, a variant associated with diminished function compared with the wild-type allele).12
Most CYP450 enzymes are expressed in the liver, but some are also expressed in significant concentrations in the gastrointestinal tract, kidney, and other sites. The main role of the CYP450 enzyme system in drug me-tabolism is to detoxify medications and to facilitate elimi-nation from the body, although toxic intermediates can occasionally be created during this process. Most of the CYP450-mediated reactions associated with drug me-tabolism occur within hepatocytes. However, enzymes present in the gastrointestinal tract can reduce oral bio-availability of some medications by degrading substrates before absorption into the bloodstream. Small subsets of enzymes are involved in the metabolic conversion of inert prodrugs to their bioactive forms. Although >50 dif-ferent CYP450 enzymes have been isolated in humans, only a select few (ie, CYP1A2, CYP2C9, CYP2C19, CY-P2D6, CYP3A4, and CYP3A5) are responsible for metab-olizing the majority of available medications.12 Of these, CYP2C9, CYP2C19, and CYP3A4 play a substantial role in statin metabolism, and CYP2C8 plays a minor role.
DDIs involving the CYP450 enzyme system are gen-erally classified as inhibition or induction interactions. Enzyme inhibition may occur as a result of direct compe-tition by substrates for available binding sites, reduced enzymatic activity, or both. The onset of enzyme inhibi-tion usually occurs rapidly after the introduction of an interacting drug. Direct competition is the most common mechanism resulting in DDIs and often occurs when 1 drug has a higher binding affinity for the enzyme or is present in significantly greater concentrations than its competing substrate. In contrast, some drugs may bind irreversibly to the enzyme and prevent its participation in subsequent metabolic reactions. Regardless of the underlying mechanism, enzyme inhibition produces in-creased serum concentrations of 1 or both medications. In the case of statin DDIs, the result is most often an increase in statin serum concentrations.
Enzyme induction occurs when a substrate enhanc-es the activity of a CYP450 enzyme. The mechanism by which induction occurs is most commonly a result of increased gene expression, often via activation of transcription factors, commonly those of the nuclear re-ceptor 1 family (eg, constitutive androstane receptor or pregnane X receptor). Other less common mechanisms include upregulation of mRNA translation and inhibition of protein degradation. Inducers frequently increase the activity of CYP450 enzymes involved in alternative meta-bolic pathways, although some may induce their own metabolism. Unlike enzyme inhibition, the peak effect of an induction reaction is often delayed for days to weeks as a result of the time required for alterations in gene expression to become evident. Inducers of the CYP450 enzyme system are less common. None of the medica-tions included in this review have been associated with CYP450 enzyme induction, although clinicians should be
Digoxin Atorvastatin Increased levels of digoxin Minor1.2-fold increase in AUC
Combination is reasonable
Diltiazem Atorvastatin Increased statin exposure/increased risk for muscle-related toxicity
Minor51% increase in AUC of atorvastatin
Combination is reasonable
Lovastatin Decreased metabolism of lovastatin leading to increased concentrationsIncreased risk of muscle-related toxicity
Moderate3.6-fold increase in AUC of lovastatin
Combination may be considered
Simvastatin Decreased metabolism of simvastatin leading to increased concentrationsIncreased risk of muscle-related toxicity
Moderate4.6-fold increase in AUC of simvastatin
Combination may be considered
Dronedarone Lovastatin Decreased metabolism of lovastatin leading to increased concentrationsIncreased statin exposure/increased risk for muscle-related toxicity
UnknownExpected to be similar to simvastatin3.9-fold increase in AUC
Combination may be considered
Simvastatin Decreased metabolism of simvastatin leading to increased concentrationsIncreased statin exposure/increased risk for muscle-related toxicity
Moderate3.9-fold increase in AUC of simvastatin
Combination may be considered
Fenofibrate/fenofibric acid
Atorvastatin Potential increase in muscle-related toxicity
Insignificant1.0-fold increase in AUC of atorvastatin
Combination is reasonable
Fluvastatin Potential increase in muscle-related toxicity
Specific data not available but magnitude likely to be minor
Combination is reasonable
Lovastatin Potential increase in muscle-related toxicity
Specific data not available but magnitude likely to be minor
Combination is reasonable
Pitavastatin Potential increase in muscle-related toxicity
Insignificant1.2-fold increase in AUC of pitavastatin
Combination is reasonable
Rosuvastatin Potential increase in muscle-related toxicity
Insignificant1.1-fold increase in AUC of rosuvastatin
Combination is reasonable
Simvastatin Potential increase in muscle-related toxicity
Insignificant1.1-fold increase in AUC of simvastatinIf taken at same time, 1.05-fold increase
Combination is reasonable
Gemfibrozil Atorvastatin† Decreased metabolism of atorvastatin leading to increased concentrationsIncreased risk of muscle-related toxicity
Minor1.4-fold increase in AUC of atorvastatin
Combination may be considered
Lovastatin Decreased metabolism of lovastatin leading to increased concentrationsIncreased risk of muscle-related toxicity
Moderate2- to 3-fold increase in AUC of lovastatin
Combination should be avoided
Pitavastatin† Decreased metabolism of pitavastatin leading to increased concentrationsIncreased risk of muscle-related toxicity
Minor1.5-fold increase in AUC of pitavastatin
Combination may be considered
Pravastatin Decreased metabolism of pravastatin leading to increased concentrationsIncreased risk of muscle-related toxicity
Moderate2.0-fold increase in AUC of pravastatin
Combination should be avoided
Rosuvastatin† Decreased metabolism of rosuvastatin leading to increased concentrationsIncreased risk of muscle-related toxicity
Minor1.6- to 1.9-fold increase in AUC of rosuvastatin
Combination may be considered
Simvastatin Decreased metabolism of simvastatin leading to increased concentrationsIncreased risk of muscle-related toxicity
Moderate2- to 3-fold increase in AUC of simvastatin
aware because this may occur with therapies used for concomitant disease states and conditions.13,14
DDIs Involving P-gpP-gp, also known as multidrug resistance-1, belongs to a superfamily of membrane-associated ATP-binding cas-sette transporters.15 Like other members of this class, P-gp uses ATP to actively pump substrates across the membrane to the extracellular space, often against a concentration gradient. P-gp expression is localized pri-marily in the gastrointestinal tract and in hepatic, renal, and brain tissue, where it plays a critical role in drug dis-position. In the gastrointestinal tract, P-gp prevents the oral absorption of medications by secreting substrates into the intestinal lumen. In renal and hepatic tissues, P-gp promotes secretion of substrates into the urine and bile, respectively. In the central nervous system, P-gp is critical to maintaining the blood-brain barrier.
As with interactions involving the CYP450 enzyme system, those involving P-gp may be broadly classified as inhibition or induction interactions. Competitive inhi-bition is the most common mechanism by which sub-strates inhibit P-gp, but mechanisms involving the regu-lation of ATP may also play a role. The consequence of P-gp inhibition depends largely on the location of the interaction. In the gastrointestinal tract, inhibition of P-gp results in enhanced drug bioavailability, whereas P-gp inhibition in hepatic and renal tissue results in reduced drug elimination. Enhanced central nervous system penetration results from inhibition of P-gp in the brain. Similar to CYP450 enzymes, induction most commonly involves enhanced gene expression. Many of the same transcription factors involved in the upregulation of CYP450 enzymes (eg, constitutive androstane receptor and pregnane X receptor) also enhance the expression of P-gp. Although reports vary, atorvastatin, lovastatin, pitavastatin, and simvastatin have been implicated as
Ranolazine Lovastatin Increased statin exposure/increased risk for muscle-related toxicity
Specific data not available but likely similar to simvastatin, which is 1.9-fold increase in AUC
Combination may be considered
Simvastatin Increased statin exposure/increased risk for muscle-related toxicity
Minor1.9-fold increase in AUC of simvastatin
Combination may be considered
Ticagrelor Atorvastatin Increased statin exposure/increased risk for muscle-related toxicity
Minor1.4-fold increase in AUC
Combination is reasonable
Lovastatin Decreased metabolism of lovastatin leading to increased concentrationsIncreased risk of muscle-related toxicity
Unknown but expected to be similar to simvastatinModerate2- to 3-fold increase in AUC
Combination may be considered
Simvastatin Decreased metabolism of simvastatin leading to increased concentrationsIncreased risk of muscle-related toxicity
Moderate2- to 3-fold increase in AUC
Combination may be considered
Verapamil Lovastatin Decreased metabolism of lovastatin leading to increased concentrationsIncreased risk of muscle-related toxicity
Moderate3.6-fold increase in AUC
Combination may be considered
Simvastatin Decreased metabolism of simvastatin leading to increased concentrationsIncreased risk of muscle-related toxicity
Moderate2.5-fold increase in AUC
Combination may be considered
Warfarin Fluvastatin Increased INR/potential for increased bleeding
Variable Combination therapy is useful
Lovastatin Increased INR/potential for increased bleeding
Variable Combination is useful
Rosuvastatin Increased INR/potential for increased bleeding
Variable Combination is useful
Simvastatin Increased INR/potential for increased bleeding
Up to 30% change in INR Combination is useful
Magnitude of drug-drug interactions based on AUC increase: minor, >1.25 to <2, moderate, ≥2 to 4.9; and severe, ≥5. AUC indicates area under the curve; and INR, international normalized ratio.
*Changes in magnitude of statin AUC are reported with cyclosporine. Limited data exist with tacrolimus, everolimus, and sirolimus (see text).†Use in combination is recommended only when other options have been exhausted.
both P-gp substrates and inhibitors.15–19 Common P-gp substrates, inducers, and inhibitors that affect statin me-tabolism are given in Table 3.12,16,20–22
Other transport proteins, including organic anion-transporting polyprotein (OATP) 1B1 (OATP1B1) and efflux transporter breast cancer resistance protein, are involved in statin uptake and metabolism.23 Similar to P-gp, breast cancer resistance protein is involved in drug efflux, whereas OATP1B1 is involved in the hepatic uptake of substrates from the portal circulation. Despite these differences in the mechanism of drug transport, the net result of inhibiting these enzymes is enhanced serum statin concentrations.
Statin MetabolismThere are a number of differences in the pharmacokinet-ic profiles of statin agents, including absorption, distri-bution, metabolism, and excretion. Clinically significant DDIs with statins often stem from a direct effect on ≥1 of these parameters. Two pharmacokinetic measures, the area under the curve (AUC) and maximum serum concen-tration (Cmax), can be altered in the presence of a DDI. Changes in these 2 pharmacokinetic measures are used
Table 2. Clinical Recommendations on Management of Select DDIs With Statins*
Interacting Medication Statin
Clinical Recommendations for Management
Amiodarone Lovastatin Limit dose of lovastatin to 40 mg daily
Simvastatin Limit dose of simvastatin to 20 mg daily
Amlodipine Lovastatin Limit dose of simvastatin and lovastatin to 20 mg dailySimvastatin
Colchicine Atorvastatin Closer monitoring for muscle-related toxicity is recommended when used in combination
Fluvastatin
Lovastatin
Pitavastatin
Pravastatin
Rosuvastatin
Simvastatin
Conivaptan Lovastatin Avoid combination
Simvastatin
Cyclosporine/tacrolimus/everolimus/sirolimus
Atorvastatin Limit dose of atorvastatin to 10 mg daily
Fluvastatin Limit dose of fluvastatin to 40 mg daily
Lovastatin Avoid combination
Pitavastatin
Pravastatin Limit dose of pravastatin to 40 mg daily
Rosuvastatin Limit dose of rosuvastatin to 5 mg daily
Simvastatin Avoid combination
Diltiazem Lovastatin Limit dose of lovastatin to 20 mg daily
Simvastatin Limit dose of simvastatin to 10 mg daily
Dronedarone Lovastatin Limit dose of lovastatin to 10 mg daily
Simvastatin Limit dose of simvastatin to 10 mg daily
Gemfibrozil Atorvastatin Combination is acceptable to use if clinically indicated and fenofibrate (or fenofibric acid) is not an option; the Figure provides additional guidance
Lovastatin Avoid combination
Pitavastatin Combination is acceptable to use if clinically indicated and fenofibrate (or fenofibric acid) is not an option; the Figure provides additional guidance
Pravastatin Avoid combination
Rosuvastatin Combination is acceptable to use if clinically indicated and fenofibrate (or fenofibric acid) is not an option; the Figure provides additional guidance
Simvastatin Avoid combination
(Continued )
Ranolazine Lovastatin Combination is acceptable to use if clinically indicated and an alternative non-CYP3A4 statin cannot be used. However, doses of lovastatin or simvastatin should not exceed 20 mg daily.
Simvastatin
Tacrolimus Atorvastatin Limit dose of atorvastatin to 10 mg daily
Fluvastatin Limit dose of fluvastatin to 40 mg daily
Lovastatin Avoid combination
Pitavastatin
Pravastatin Limit dose of pravastatin to 40 mg daily
Rosuvastatin Limit dose of rosuvastatin to 5 mg daily
Simvastatin Avoid combination
Ticagrelor Atorvastatin Combination is acceptable without dose limitations
Lovastatin Limit dose of lovastatin to 40 mg daily
Simvastatin Limit dose of simvastatin to 40 mg daily
Verapamil Lovastatin Limit dose of lovastatin to 20 mg daily
Simvastatin Limit dose of simvastatin to 10 mg daily
Fenofibrate (or fenofibric acid) is the preferred fibrate to use in combination with statins. CYP indicates cytochrome.
*Select statin-drug interactions discussed in the article that do not appear in the table are not considered clinically significant.
by the US Food and Drug Administration (FDA) to define the presence of a DDI. The AUC is specifically the cal-culated area under the plasma-drug concentration-time curve and reflects total body exposure to a medication after administration. The Cmax, the highest drug con-centration achieved after administration of a medication, is a marker of peak drug exposure at a specific time. Table 4 compares the pharmacokinetic properties of the 7 currently available statin agents.24–32 For the purpose of making clinical recommendations for the manage-ment of DDIs involving statins, an increase in the AUC should be used because it has been recommended in the application of the results of DDI studies. The level of increase in the AUC and the magnitude of the interaction is defined as minor (>1.25–<2.0), moderate (≥2–4.9), or severe (≥5).33
AbsorptionBioavailability is defined as the percentage of the statin dose that is absorbed and reaches the systemic circu-lation after absorption. Systemic bioavailability is gen-erally considered low for all statins. Pitavastatin has the highest bioavailability (43%–51%); simvastatin and lovastatin have very low bioavailability (<5%). Impor-tantly, bioavailability is relatively consistent with most statins whether administered with or without food, making differences in this pharmacokinetic parameter noncontributory. However, the overall bioavailability of
lovastatin is decreased by ≈50% when given without food. The time to peak concentration after absorption is relatively short with all statins (within 4 hours) when given in their immediate-release formulations. DDIs with statins typically are not attributable to changes in absorption.
DistributionDistribution of drug throughout the body is another im-portant pharmacokinetic parameter. Protein binding influences drug distribution and ultimately the pharma-cological effects of drugs because only the unbound or free drug is able to elicit targeted effects. Most statins except pravastatin are highly protein bound. Another as-pect of drug distribution, considered a chemical prop-erty, is lipophilicity, which is measured in log P. Statins with a log P value >0 have greater drug penetration into fat than into water. All statins except pravastatin and ro-suvastatin are considered lipophilic. Although adverse effects may be influenced by differences in drug distri-bution, DDIs with statins typically are not attributable to changes in drug distribution.
MetabolismThe most diverse pharmacokinetic parameter among statins is metabolism. In general, lipophilic statins require a greater degree of metabolism to convert the statin into hydrophilic (water soluble) salts and conjugates that
Table 3. Common P-gp Substrates, Inhibitors, and Inducers Associated With the CyP450 Enzymes Affecting Statin Metabolism12,16,20–22
are eliminated from the body. One metabolic pathway is glucuronidation, which results in statin conversion to glucuronide conjugates. This metabolic pathway can be inhibited by certain nonstatin medications (eg, gemfibro-zil) and can result in increases in systemic drug expo-sure with all statins to various degrees.
The primary form of drug metabolism for most statins occurs through CYP450 enzymes. The most prevalent CYP450 enzyme subcategories for statin metabolism are the 3A4 and 2C9 enzyme systems. Simvastatin and lovastatin undergo significant CYP3A4 metabolism, and atorvastatin undergoes a lesser amount as one of its mi-nor metabolic pathways. This is in contrast to fluvastatin, pitavastatin, and rosuvastatin, which require CYP2C9. Because CYP3A4 is the most common enzyme involved in drug metabolism, simvastatin and lovastatin will have more DDIs that will likely require intervention.
Pravastatin is the only statin that does not undergo CYP450 metabolism. A number of medications copre-scribed in patients with ASCVD can alter the metabolism of statins through the CYP450 metabolic pathway as inducers, inhibitors, or competitive substrates. The clini-cal relevance of these types of DDIs is based on the de-gree of inhibition or induction of CYP450 and the phar-macokinetic profile of the individual statin. The majority of DDIs with statins are typically the result of changes in drug metabolism.
ExcretionStatins undergo extensive metabolism; therefore, the amount of statin that is excreted in its unchanged form through renal elimination is small. The overall de-pendence of statin metabolites on renal elimination is modest, with pravastatin being the highest at 20% and atorvastatin being the lowest at <2%. Drug elimination t1/2, the time it takes to reduce the systemic drug con-
centration by 50%, predicts the time course of overall drug elimination. Fluvastatin, lovastatin, pravastatin, and simvastatin have a relatively short t1/2. These agents are optimally dosed in the evening or administered as an extended-release formulation (for fluvastatin or lov-astatin) to maximize effect. In contrast, atorvastatin, pitavastatin, and rosuvastatin have longer half-lives and can be dosed at any time of the day. Statins are also excreted into bile and feces as a means of drug elimi-nation. This excretion is facilitated by OATPs. Similar to CYP450, there are several subtypes of OATP that can affect the elimination of rosuvastatin and pitavas-tatin.28,30 DDIs with statins may sometimes be attribut-able to decreased drug excretion, especially in patients with impaired glomerular filtration rate, and are related to the extent the statin is renally excreted. This potential issue is limited with atorvastatin, which has the least amount of renal excretion (<2%), but may be a consid-eration for other statins that have a higher degree of renal excretion (eg, pitavastatin, pravastatin, rosuvas-tatin, simvastatin).
DDIs WITH NONSTATIN LIPID-LOWERING AGENTSFibric Acid Derivatives (Fibrates)Coadministration of a statin with a fibrate may some-times be warranted for the treatment of complex dys-lipidemias or severe hypertriglyceridemia, particularly in patients with obesity, metabolic syndrome, insulin resistance, or diabetes mellitus. In the United States, gemfibrozil, fenofibrate, and fenofibric acid are the only fibrates approved for clinical use. Both statins and fi-brates have been independently associated with a risk of muscle-related toxicity as monotherapy, and statin-
Table 4. Pharmacokinetic Properties of Statins24–32
Absorption Distribution Metabolism Excretion
bioavailability,%
Tmax,h
Proteinbinding,
%Lipophilicity,
log PMajor P450
Hepatic Enzyme ProdrugActive
Metabolites
Renal Excretion,
% t1/2, h
Atorvastatin 14 1–2 ≥98 4.1 CYP3A4 No Yes <2 14
Fluvastatin 24 <1 98 3.24 CYP2C9(CYP2C8 and
CYP3A4 are minor)
No No 5 3
Lovastatin <5 2–4 >95 4.3 CYP3A4 Yes Yes 10 2–3
Pitavastatin 43–51 1 99 1.5 CYP2C9(CYP2C8 is minor)
No No 15 12
Pravastatin 17 1–1.5 50 −0.2 Non-CYP No No 20 1.8
Rosuvastatin 20 3–5 88 −0.3 CYP2C9 No Minimal 10 19
Simvastatin <5 4 95 4.7 CYP3A4 Yes Yes 13 2
CYP indicates cytochrome P; t1/2
, drug half-life; and Tmax
, amount of time that a drug is present at the maximum concentration in serum.
fibrate combination therapy increases this risk.34–39 Epi-demiological studies have estimated that monotherapy with a fibrate is associated with a 5.5-fold increased risk of muscle-related toxicity compared with statin therapy alone.40 Muscle-related toxicity has been reported with both available fibrates when used in combination with statins but occurs more frequently with gemfibrozil.41.42 However, in large clinical trials with gemfibrozil mono-therapy, including VA-HIT (Veterans Affairs-High-Density Lipoprotein Intervention Trial; n=2531) and HHS (Helsin-ki Heart Study; n=4081), there were no reported cases of rhabdomyolysis.43,44
The increased risk of muscle-related toxicity with statin-fibrate combination therapy was first reported with the combination of gemfibrozil and lovastatin in 1990 but has subsequently been demonstrated with other fi-brates and with most statins, particularly cerivastatin, which has been removed from the market.45,46 According to evidence from the FDA Adverse Event Reporting Sys-tem database, reports of muscle symptoms were 15.7 per 1 million prescriptions for gemfibrozil compared with 8.8 per 1 million for fenofibrate (odds ratio, 1.78; P<0.0001), and the rate of gemfibrozil-associated rhab-domyolysis was ≈10-fold higher compared with fenofi-brate.47 This dramatic difference in reports of rhabdo-myolysis between the 2 fibrates appeared to be driven largely by an increased risk in patients taking gemfibrozil with a statin. The increase in risk with coadministration of fibrates and statins is greater than the predicted sum of the monotherapy risks, suggesting both pharmacoki-netic and pharmacodynamic causal mechanisms.48
GemfibrozilGemfibrozil is rapidly absorbed after oral administration with nearly 100% bioavailability, reaching peak plasma concentrations within 1 to 2 hours. It is highly protein bound, has an elimination t1/2 of ≈1.5 hours, and is dosed twice daily.49 The active drug undergoes conjugation to its acyl glucuronide, gemfibrozil 1-0-β glucuronide, which is then oxidized via the CYP450 system.50,51 The majority of the gemfibrozil dose is eliminated as the glucuronide conjugate in the urine with little excreted as unchanged gemfibrozil.
Gemfibrozil and particularly its glucuronide metabo-lite are potent irreversible inhibitors and inactivators of CYP2C8.37 Both are substrates but not inhibitors of CYP3A4. Gemfibrozil 1-0-β glucuronide and, to a lesser extent, the parent compound are also potent inhibitors of OAT1B1/3-mediated hepatic uptake of statin acids, as well as OATP2B1, Na+-taurocholate cotransporting polypeptide, the renal transporter OAT3, and statin gluc-uronidation or lactonization.52,53 Thus, DDIs, including hepatotoxicity and muscle-related toxicity, in patients re-ceiving statin-gemfibrozil combination therapy may vary as a result of differences in statin susceptibility to inhibi-
tory effects of intestinal, hepatic, and renal transporters, as well as CYP450 metabolism.
Gemfibrozil increases the AUC of active simvastatin acid and lovastatin acid by ≈2- to 3-fold.54,55 The AUC values of atorvastatin and its active metabolites (2-hy-droxyatorvastatin, 2-hydroxyatorvastatin lactone, 4-hy-droxyatorvastatin lactone) are modestly (1.2- to 1.4-fold) but significantly increased when coadministered with gemfibrozil.40,56,57 It is suggested that these interactions are likely attributable to the inhibition of OATP2-mediated hepatic uptake because these agents are metabolized by CYP3A4, which is not significantly affected by gemfibrozil.
Pravastatin is more hydrophilic than other statins and does not easily cross cell membranes, relying on transporters for absorption, tissue uptake, and elimina-tion. The drug is minimally metabolized and is not sig-nificantly eliminated via CYP450 enzymes. Renal elimi-nation accounts for 20% of total clearance. However, pravastatin-gemfibrozil combination therapy increases plasma pravastatin concentrations by 202% (range, 40%–412%) and significantly reduces renal clearance of the drug from 25 to 14 L/h (P<0.0001) in healthy volun-teers.58 These findings are consistent with the inhibition of OATP1B1-mediated uptake and inhibition of the renal transporter OAT3.
Active uptake via the OATP1B1/3, Na+-taurocholate cotransporting polypeptide, breast cancer resistance protein, and active renal tubular secretion via OAT3 are also important for the elimination of rosuvastatin. Rosu-vastatin is not extensively metabolized and is primarily eliminated unchanged in urine and feces. Consistent with other statins reviewed above, gemfibrozil increased plasma concentrations of rosuvastatin by ≈1.56- to 1.88-fold.59,60 Gemfibrozil had only a modest effect when administered with pitavastatin in 24 subjects with an in-crease of 45% in the AUC.61 Metabolism is only a minor pathway for pitavastatin via CYP2C9, which is unaffected by gemfibrozil. Fluvastatin transport in hepatocytes via the OATP transporters is potently inhibited by gemfibro-zil.62 However, in at least 1 study of 17 subjects, no sig-nificant difference was observed in the AUC and Cmax in a comparison of the gemfibrozil-fluvastatin combination and gemfibrozil alone.63
The 2013 American College of Cardiology/Ameri-can Heart Association “Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Risk in Adults” states that combination therapy with any statin and gemfibrozil should be avoided.10 This recommen-dation is because of concerns for the increased risk for muscle-related toxicity.46 However, despite these recommendations, a recent analysis of a nationwide register study found that although providers were less likely to prescribe gemfibrozil, the mean dose of statin was substantially higher in those on a statin-gemfibrozil regimen.64 The American College of Cardiology/Ameri-can Heart Association recommendation was derived
from primary and secondary prevention trials evaluat-ing statins in which patients with serious comorbidi-ties and those taking concomitant medications (includ-ing gemfibrozil) that may increase the risk of statin muscle-related toxicity were excluded. However, cost considerations, drug availability, and tolerability may make avoidance of this combination difficult for some patients. Pharmacokinetic evidence suggests that the magnitudes of the interactions between gemfibrozil and atorvastatin, pitavastatin, and rosuvastatin are minor and the magnitudes of the interactions between gem-fibrozil and lovastatin, pravastatin, and simvastatin are moderate. Given the results of pharmacokinetic data, the combination of gemfibrozil with specific statins may be considered if clinically indicated. An algorithm is pro-vided in the Figure for general guidance on how to opti-mize safety and efficacy when cost issues necessitate combination therapy.
It is important to note that observational studies clearly demonstrate that the risk of muscle-related toxicity is significantly lower with statin-fenofibrate/fenofibric acid combination therapy compared with statin-gemfibrozil combination therapy. The FDA-approved product labeling recommends that the combined use of gemfibrozil with lo-vastatin, fluvastatin, pravastatin, pitavastatin, atorvastatin, and rosuvastatin should be avoided. 24–28,30 However, the FDA-approved product labeling for simvastatin indicates that gemfibrozil is contraindicated with simvastatin.29
Fenofibrate/Fenofibric AcidFenofibrate is a prodrug, the ester of fenofibric acid. Ester hydrolysis converts fenofibrate to fenofibric acid, the active chemical moiety.65,66 The drug may be admin-istered as either a prodrug (fenofibrate) or the active metabolite (fenofibric acid). Both agents are well ab-sorbed from the gastrointestinal tract with peak plasma concentrations within 6 to 8 hours (fenofibrate) or 4 to 5 hours (fenofibric acid). Fenofibric acid undergoes gluc-uronidation and is excreted in the urine primarily as the fenofibric glucuronide. Neither compound undergoes oxi-dative CYP450 metabolism. The elimination t1/2 of both medications is 20 hours. Dose adjustments are recom-mended for patients with mild to moderate renal impair-ment, and the use of both drugs should be avoided in severe renal impairment because of a 2.7-fold increase in the AUC when estimated glomerular filtration is <30 mL·min−1·1.73 m−2.35,67
Fenofibric acid and fenofibrate do not inhibit CYP3A4, CYP2D6, CYP2E1, or CYP1A2; are weak inhibitors of CYP2C8, CYP2C19, and CYP2A6; and are mild to mod-erate inhibitors of CYP2C9. No significant effects on oxidation, glucuronidation, or plasma concentrations of statins have been identified when fenofibrate is adminis-tered in combination with statins.68–71
Data from the FDA Adverse Event Reporting System indicate that the number of reports of rhabdomyolysis per 1 million prescriptions was ≈15 times lower for feno-fibrate than for gemfibrozil when prescribed with statins other than cerivastatin (0.58 per 1 million for fenofibrate versus 8.6 per 1 million for gemfibrozil).42
In the FIELD study (Fenofibrate Intervention and Event Lowering in Diabetes; n=9795), none of the ≈1000 pa-tients on statin-fenofibrate combination therapy experi-enced rhabdomyolysis.72 In the ACCORD study (Action to Control Cardiovascular Risk in Diabetes), there were no statistically significant differences in the incidence of myositis, rhabdomyolysis, or elevations of hepatic trans-aminases with simvastatin-fenofibrate combination ther-apy compared with simvastatin monotherapy in patients with type 2 diabetes mellitus.73
The expert panel of the 2013 American College of Cardiology/American Heart Association blood cholester-ol guideline recommended that “Fenofibrate may be con-sidered concomitantly with a low- or moderate-intensity statin only if the benefits from ASCVD risk reduction or triglyceride lowering when triglycerides are ≥500 mg/dL are judged to outweigh the potential risk for adverse effects.”10
Summary of Evidence for Statin-Fibrate DDIsOn the basis of pharmacokinetic evidence, the combi-nation of gemfibrozil with lovastatin, pravastatin, and simvastatin is potentially harmful and should be avoid-ed. Although gemfibrozil interacts with atorvastatin, pitavastatin, and rosuvastatin, the result is only a minor increase in statin concentrations, and the combination may be considered if clinically indicated. Fluvastatin may be used in combination with gemfibrozil without any spe-cific dose limitations, and this particular statin does not interact with gemfibrozil. Combination therapy with feno-fibrate/fenofibric acid and any statin is reasonable when clinically indicated.
Recommendations for Statin-Fibrate DDIs1. When statin-fibrate combination therapy is
indicated, fenofibrate or fenofibric acid is pre-ferred because of a reduced incidence of DDIs compared with statin-gemfibrozil combination therapy.
2. There are circumstances in which gemfibrozil may be the only available fibrate, cost may be a consid-eration, or fenofibrate may not be tolerated. Under any circumstance, the use of gemfibrozil should be avoided in combination with lovastatin, pravas-tatin, and simvastatin.
3. If gemfibrozil must be used in combination with atorvastatin, pitavastatin, or rosuvastatin, consid-eration should be given to the use of a low statin
dose to minimize risk. For example, the use of rosuvastatin in combination with gemfibrozil is included in the FDA-approved product labeling, but the labeling requires that the daily dose of rosuvas-tatin be limited to 10 mg daily.
4. Fluvastatin may be used in combination with gem-fibrozil, fenofibrate, or fenofibric acid.
NiacinNiacin (nicotinic acid), a naturally occurring, water-solu-ble vitamin of the B complex (vitamin B3), has been stud-ied extensively both as monotherapy for hypercholester-olemia and in combination with other therapies for the management of complex dyslipidemias. However, on the basis of currently available evidence of nonefficacy and
Figure. Algorithm for treating patients with statin-fibrate combination therapy.Blue boxes indicate where it is acceptable to proceed with combination therapy. Yellow boxes indicate where caution should be used when combination therapy is considered. Red boxes indicate where combination therapy should not be used. CK indicates creatinine kinase; CrCL, creatinine clearance; HTG, hypertriglyceridemia; TG, triglyceride; and ULN, upper limit of normal.
potential harms, there are currently no clear indications for the routine use of niacin preparations in combination with statins.74,75 Therefore, niacin is not considered in this document.
CALCIUM CHANNEL bLOCkERSCalcium channel blockers (CCBs) selectively inhibit volt-age-gated L-type channels on cardiac myocytes, cardiac cells in the sinoatrial and atrioventricular nodes, and vascular smooth muscle cells peripherally. CCBs have a significant role in the treatment of several cardiovascular conditions such as hypertension, chronic stable angina, and supraventricular arrhythmias.76–78 Because of clearly defined cardiovascular benefits, CCBs are often copre-scribed in patients treated with statin therapy.
There are 2 recognized subclasses of CCBs based on their chemical structure, the dihydropyridines (eg, amlodipine, felodipine) and the nondihydropyridines (diltiazem and verapamil). Dihydropyridine CCBs have more specific selectivity for vascular smooth muscle cells peripherally than cardiac cells, so their primary treatment roles are in the treatment of hypertension and chronic stable angina. Nondihydropyridine CCBs have greater selectivity for myocardial cells, resulting in a decrease in sinoatrial and atrioventricular node conduction and decreased myocardial contractility. Nondihydropyridine CCBs are used primarily to treat hypertension, chronic stable angina, and supraventricu-lar arrhythmias.
Diltiazem and verapamilDiltiazem and verapamil are moderate to weak inhibi-tors of CYP3A4, as well as substrates of CYP3A4 and P-gp. Increased exposure to simvastatin, atorvastatin, and lovastatin when coadministered with diltiazem and verapamil has been reported.79–83 In 10 healthy volun-teers, diltiazem increased the Cmax of simvastatin by 3.6-fold and simvastatin acid by 3.7-fold (P<0.05).84 The AUC of simvastatin was increased by 5-fold (P<0.05) and the elimination t1/2 by 2.3-fold (P<0.05). In a study of 10 healthy volunteers, diltiazem significantly (P<0.05) increased the AUC of lovastatin by 3.6-fold and Cmax from 6±2 to 26±9 ng/mL but did not change the elimi-nation t1/2.
85 Rhabdomyolysis has been reported in a pa-tient on stable treatment with atorvastatin after diltiazem was added for the new diagnosis of atrial fibrillation.86 In animal studies, simvastatin significantly enhanced the oral bioavailability of verapamil.87
AmlodipineAmlodipine is a substrate of CYP3A4, and its plasma concentrations may be affected by inhibitors or induc-ers of this enzyme. Coadministration of multiple doses
of 10 mg amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared with simvastatin alone.29 However, coadministration of amlodipine with 80 mg atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.24 In the ALLHAT-LLT trial (The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid-Lowering Treatment), 1122 patients (21.7%) took amlodipine in combination with pravastatin, and no incidence of muscle-related toxicity was reported.88
The FDA-approved product labeling for amlodipine indicates that there may be an increased risk of muscle-related toxicity when combined with simvastatin.89 The approved labeling for diltiazem recommends the use of non–CYP3A4-metabolized statins in combination with diltiazem if possible.90 Current labeling advises that the dose of simvastatin not exceed 10 mg daily when copre-scribed with diltiazem or verapamil in adult patients and the dose of lovastatin not exceed 20 mg daily26,29 The product labeling for atorvastatin does not include dose adjustments for combination therapy with amlodipine, dil-tiazem, or verapamil.24 However, labeling for verapamil recommends that with coadministration lower doses of atorvastatin may be considered.91
Summary of Evidence for Statin-CCb DDIsPharmacokinetic data suggest a minor increase in statin exposure with coadministration of amlodipine and lov-astatin or simvastatin, and combination therapy may be considered. There is no evidence of significant in-teraction when amlodipine is coadministered with other statins. Combination therapy with atorvastatin and diltia-zem results in a minor increase in statin exposure and is reasonable in appropriate patients. Interactions be-tween diltiazem and either lovastatin or simvastatin are associated with moderate increases in statin exposure, although combination therapy may be considered in ap-propriate patients. DDIs with verapamil and lovastatin or simvastatin are also of moderate intensity. Combination therapy may be considered when the potential for ben-efit outweighs potential risks.
Recommendations for Statin-CCb DDIs1. Pharmacokinetic data suggest a minor increase in
statin exposure with coadministration of either lov-astatin or simvastatin with amlodipine, and these combination therapies may be considered.
2. There is no evidence of significant interaction when amlodipine is coadministered with atorvas-tatin, pitavastatin, rosuvastatin, fluvastatin, and pravastatin, and these combination therapies may be considered.
3. Combination therapy with atorvastatin and diltia-zem results in a minor increase in statin exposure and this combination therapy is reasonable.
4. Diltiazem administered with either lovastatin or sim-vastatin is associated with moderate increases in statin exposure, although these combination thera-pies may be considered in appropriate patients.
5. Coadministration of verapamil with lovastatin or simvastatin results in moderate increases in statin exposure. Therefore, these combination therapies may be considered when the potential for benefit outweighs potential risks.
6. Doses of lovastatin or simvastatin >20 mg daily when coadministered with amlodipine are not recommended.
7. A non–CYP3A4-metabolized statin is preferred in combination with diltiazem or verapamil.
8. Doses of simvastatin >10 mg daily and doses of lovastatin >20 mg daily. when used with diltiazem or verapamil are not recommended. However, it should be noted that verapamil labeling recom-mends a higher dose limit of lovastatin of 40 mg daily when coadministered with verapamil.
9. For adult patients on stable therapy with simvas-tatin 80 mg daily (a dose that is no longer recom-mended for general use), clinicians should change to a non-CYP3A4 statin such as pravastatin, rosu-vastatin, or pitavastatin if therapy with diltiazem or verapamil is initiated.
10. Caution should be exercised with statin-CCB com-bination therapy in patients of various ethnic back-grounds, particularly those of Asian descent.
ANTIARRHyTHMIC AGENTSIn patients with known ASCVD and multiple risk factors, antiarrhythmic agents may be prescribed for the man-agement of supraventricular and ventricular arrhyth-mias, particularly atrial fibrillation and ventricular tachy-cardia/fibrillation. Concomitant therapy with statins and amiodarone or dronedarone is common, and DDIs are an important consideration.92 Amiodarone and droneda-rone are Vaughan-Williams class III antiarrhythmic drugs, which uniquely affect multiple ion channels and exhibit properties of class I through IV agents.93 Both amioda-rone and dronedarone prolong the duration of the action potential and the refractory period of atrial, nodal, and ventricular cardiac fibers.
AmiodaroneAmiodarone has been used for >50 years as an antiar-rhythmic and antianginal medication. It is the most ef-fective medication in maintaining normal sinus rhythm in patients with atrial fibrillation. Amiodarone is metabo-lized by CYP3A4 and CYP2C8 to desethylamiodarone.
Amiodarone and its metabolite are inhibitors of CYP3A4 (irreversibly and weakly for amiodarone; in a competitive manner and potently for desethylamiodarone) and P-gp (in a reversible manner), causing concern for interac-tions when used concomitantly with statins metabolized by this CYP450 pathway or substrates of the P-gp efflux transporter. There is also inhibition of CYP1A2, CYP2C9, and CYP2D6.94
There have been multiple reports of toxicity when ami-odarone is prescribed in combination with statins that are CYP3A4 substrates, particularly simvastatin.92,95–102 Pharmacokinetic data show an ≈75% increase in simv-astatin and the active simvastatin acid AUC and Cmax when amiodarone and simvastatin are coadministered, but no significant pharmacokinetic interaction between amiodarone and pravastatin has been demonstrated.103 In the SEARCH (Study Evaluating Additional Reduction in Cholesterol and Homocysteine), of 12 064 survivors of myocardial infarction, 8 cases of myopathy and 7 cases of rhabdomyolysis were identified in patients on simvastatin 80 mg in combination with amiodarone versus zero cases in patients allocated to simvastatin 20 mg (relative risk, 8.8; 95% confidence interval, 4.2–18.4).104 As a result of an early interim review by the Data Safety Monitoring Board for SEARCH, changes to the labeling for simvastatin were approved in May 2002 recommending that the dose of simvastatin be limited to 20 mg in patients concomitantly taking amio-darone.29
In large clinical outcomes trials of amiodarone in patients conducted in the 1990s, concomitant therapy with statins is not mentioned, and no cases of muscle-related toxicity were reported.105–108 In another trial in which 19% of patients were taking concomitant statin and amiodarone, again no cases of rhabdomyolysis were reported.109 However, specific statins and doses were not reported. A review of the FDA database from 1990 through March 2002 examined cases of adverse events reported for concomitant therapy with amio-darone and simvastatin, atorvastatin, or pravastatin.92 Muscle-related toxicity was the most commonly report-ed adverse event with combination therapy (77%) and tended to occur in older male patients taking multiple other medications. The percentages of simvastatin and atorvastatin adverse events reported in which amiod-arone was concomitantly used were 1.0% and 0.7%, respectively (P=NS between statins). In contrast, the percentage of pravastatin adverse events in which amiodarone was used was only 0.4% (P<0.05 versus simvastatin). Patients on simvastatin-amiodarone com-bination therapy were more likely to be hospitalized and were on a higher statin dose compared with atorvas-tatin-amiodarone–treated patients.
Despite labeling changes for simvastatin that oc-curred in 2002 to limit doses when used in combina-tion with amiodarone and other select medications,
coadministration continues to occur. In a retrospective analysis of a longitudinal prescription claims database of concurrent statin-amiodarone therapy dispensed during 2006, nearly half (44%) of patients on amio-darone were also prescribed a statin (atorvastatin, 23.5%; simvastatin, 13.3%).110 A safety initiative was begun in a Veterans Affairs Medical Center in Novem-ber 2008 to assess the number of patients with active prescriptions with both simvastatin at doses >20 mg daily and amiodarone.111 Of the 17 760 patients with an active prescription for simvastatin 40 or 80 mg, 92 patients (0.52%) were also on therapy with amioda-rone. The mean duration of simvastatin 40 or 80 mg daily and amiodarone was 43 months. In an observa-tional, retrospective analysis of inpatients on a cardiol-ogy service in a teaching university hospital, potential statin-drug interactions were reviewed from July 2007 to June 2008.112 Of the 1641 hospitalized patients, 572 were prescribed a statin, most commonly simvas-tatin. The exposure to potential statin-drug interactions was 26.1% at admission and 24.4% at discharge. Ami-odarone was the most common CYP450 3A4 inhibitor coprescribed with statins.
The FDA-approved labeling for rosuvastatin, pravas-tatin, fluvastatin, and pitavastatin does not indicate that a dose adjustment in necessary when coadministered with amiodarone.25,27,28,30 Additionally, no dose adjust-ments are recommended for atorvastatin because data suggest that severe interactions with amiodarone are less likely to occur than with other statins metabolized via CYP3A4 (simvastatin, lovastatin).24,26,29 However, la-beling indicates that the dose of lovastatin should not exceed 40 mg daily when prescribed in combination with amiodarone and simvastatin and should be limited to no more than 20 mg daily.
DronedaroneDronedarone is a class III antiarrhythmic indicated to reduce the risk of hospitalization for atrial fibrilla-tion in patients who are currently in sinus rhythm and have a history of paroxysmal or persistent atrial fibril-lation.94,113 Dronedarone is a structurally related, non-iodinated derivative of amiodarone. Dronedarone is available only for oral administration, and the absolute bioavailability is increased 2- to 3-fold when adminis-tered with food, particularly a high-fat meal. Droneda-rone is less lipophilic than amiodarone with a smaller volume of distribution.114 Peak plasma concentrations are reached within ≈3 to 6 hours, and steady state is achieved within 4 to 8 days. The elimination t1/2 is 13 to 19 hours.
Dronedarone is extensively metabolized by CYP3A4 to >30 metabolites, most inactive. The N-debutyl metab-olite is weakly active and only 1/10th to 1/3rd as potent as dronedarone. It is excreted primarily as metabolites
in the feces (84%), with only 6% excreted in the urine. Dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6 and has the potential to inhibit P-gp transport. There are no significant effects on OAT1, OAT3, OCT1, CYP1A2, CYP2C9, CYP2C19, CYP2C8, or CYP2B6. As a moderate CYP3A4 inhibitor, dronedarone significantly increases the Cmax and AUC of simvastatin and simv-astatin acid.94 However, no dose adjustments of drone-darone are necessary when given in combination with atorvastatin or simvastatin.
Concomitant statin-dronedarone therapy was report-ed in 22% to 39% of patients in the ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid or the Prevention of Cardiovascular Hospitalization or Death From Any Cause in Patients With Atrial Fibrillation/Atrial Flutter), EURIDIS (European Trial in Atrial Fibrillation or Flutter Pa-tients Receiving Dronedarone for the Maintenance of Si-nus Rhythm), ADONIS (American-Australian-African Trial With Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm), and DIONYSOS (Randomized, Double-Blind Trial to Evaluate the Efficacy and Safety of Dronedarone [400 mg bid] Versus Ami-odarone [600 mg qd for 28 days, Then 200 mg qd Thereafter] for at Least 6 months for the Maintenance of Sinus Rhythm in Patients With AF) trials.114–116 Despite frequent statin-dronedarone combination therapy, none of these studies provided information on specific statins prescribed or the relationship of combination therapy and adverse events. There were no reports of muscle-related adverse effects.
The FDA-approved labeling for rosuvastatin, atorvas-tatin, pitavastatin, fluvastatin, and pravastatin does not recommend any contraindications or dose adjustments when coadministered with dronedarone.24,25,27,28,30 Cur-rent FDA labeling recommends a dose limit of simvas-tatin 10 mg daily and lovastatin 20 mg daily when com-bined with dronedarone.26,29
DigoxinDigoxin is used as a rate-controlling agent in patients with atrial fibrillation and as an inotrope in patients with heart failure with reduced ejection fraction. In heart fail-ure, digoxin exerts its effect by inhibiting the sodium-potassium ATPase pump in myocardial cells. This pro-duces a transient increase in intracellular calcium that in turn results in an influx of calcium to increase myocar-dial contractility. In atrial fibrillation, digoxin suppresses atrioventricular node conduction to increase the effec-tive refractory period and to decrease conduction veloc-ity. Digoxin has a bioavailability of ≈60% to 80%.117 The onset of effect is observed within 1 to 3 hours after oral absorption, and digoxin has an elimination half-life of 36 to 48 hours. Approximately 50% to 70% of the drug is excreted unchanged in the urine. The metabolism of di-
goxin is not dependent on the CYP450 system because it is not known to induce or inhibit any of these enzymes. Metabolism of digoxin is primary by gut bacteria.
In a study that included 24 healthy volunteers, the addition of atorvastatin 80 mg to digoxin resulted in an average increase of 20% in the Cmax of digoxin and an average 15% increase in the AUC of digoxin.118 Howev-er, lower doses of atorvastatin (10 mg) combined with digoxin did not alter the pharmacokinetics of digoxin.99 Atorvastatin appears to be the only statin that is report-ed to have this interaction. The mechanism is not fully understood but may be mediated by an impact of ator-vastatin on the intestinal secretion of digoxin medicated by the P-gp efflux transporter, resulting in increased di-goxin absorption.118
Summary of Evidence for Statin–Antiarrhythmic Agent DDIsOn the basis of pharmacokinetic and observational data and adverse events reported in randomized, controlled trials, combination therapy with amiodarone and rosuv-astatin, atorvastatin, pitavastatin, fluvastatin, or pravas-tatin is reasonable. Coadministration of amiodarone and dronedarone with either lovastatin or simvastatin may be considered. There are no known clinically significant in-teractions between dronedarone and other statins.
Digoxin coadministration with any statin is reasonable if clinically indicated.
Recommendations for Statin–Antiarrhythmic Agent DDIs
1. Combination therapy with rosuvastatin, atorvas-tatin, pitavastatin, fluvastatin, or pravastatin and amiodarone is reasonable.
2. When used in combination with amiodarone, the dose of lovastatin should not exceed 40 mg daily and the dose of simvastatin should not exceed 20 mg daily.
3. Digoxin coadministration with any statin is reason-able if clinically indicated.
4. Higher doses of lovastatin and simvastatin may be considered if clinically indicated with close moni-toring for muscle-related toxicity.
5. In patients who are already stable on lovastatin 80 mg daily or simvastatin ≥40 mg daily in combina-tion with amiodarone, continuation of combination therapy is reasonable without dose modifications.
6. Dronedarone significantly increases systemic expo-sure of both the prodrug simvastatin and the active metabolite simvastatin acid. Therefore, the dose of simvastatin should be limited to 10 mg daily when used in combination with dronedarone.
7. Although there are no specific studies evaluating lovastatin and dronedarone, it is anticipated that
dronedarone may also increase the exposure of lovastatin within the same range as simvastatin.
8. There are no clinically significant interactions between dronedarone and other statins, and these combination therapies are reasonable.
9. Atorvastatin is the only statin that appears to be associated with a potential DDI when used in com-bination with digoxin. On the basis of the available data, patients on higher doses of atorvastatin may be at increased risk of digoxin toxicity, and closer monitoring for digoxin toxicity is recommended.
ANTIANGINAL AGENTSRanolazineRanolazine is a unique antianginal medication with a mechanism of action that remains unknown. Ranolazine is metabolized predominantly by CYP3A4 and to a less-er extent by CYP2D6, and it is also a weak inhibitor of CYP3A4.119 As a result, some statins, particularly sim-vastatin, are of concern for drug interactions. Simvas-tatin-ranolazine combination therapy results in an ≈50% increase in AUC and doubling of Cmax of simvastatin.120 The impact of this increased statin exposure on the risk of muscle-related toxicity in not clear. However, there have been at least 3 case reports, some of which are in elderly patients.81,121–123 Clinically significant DDIs with ranolazine and statins other than simvastatin have not been reported.124–127
The FDA-approved product labeling recommends that the maximum dose of simvastatin be limited to 20 mg daily when given in combination with ranolazine. Although evidence for statin interactions with ranola-zine is most abundant with simvastatin, reasonable concern could be extrapolated to other statins that are metabolized by CYP3A4. Caution is recommended when lovastatin is used in combination with ranola-zine, although no specific dose limitation is recom-mended.26
Summary of Evidence for Statin-Ranolazine DDIsCoadministration of ranolazine with rosuvastatin, atorv-astatin, pitavastatin, fluvastatin, and pravastatin may be considered if clinically indicated. Combination therapy with ranolazine and simvastatin or lovastatin may be considered.
Recommendations for Statin-Ranolazine DDIs1. Coadministration of rosuvastatin, atorvastatin,
pitavastatin, fluvastatin, or pravastatin with rano-lazine may be considered if clinically indicated.
2. The dose of simvastatin should be limited to 20 mg daily when coprescribed with ranolazine, and doses above this limit are not recommended.
3. Given that simvastatin and lovastatin undergo simi-lar metabolism, it is reasonable to limit the dose of lovastatin to 20 mg daily when combined with ranolazine.
ANTICOAGULANTSWarfarinWarfarin is a vitamin K antagonist and the most com-monly used oral anticoagulant with important roles in treating many patients with cardiovascular disease. It is also a classic example of a medication with a narrow therapeutic window and is subject to significant DDIs. Interactions between statins and warfarin are modest when viewed in the context of other potential interact-ing medicines; however, both classes of medications are commonly used. Potential interactions are thought to act predominantly via drug metabolism through a contribu-tion of protein-binding effects. Warfarin is metabolized to inactive products primarily by CYP2C9, which has a minor role in the metabolism of fluvastatin and rosuv-astatin.128 The majority of reports and studies have fo-cused on the potential for impact on the anticoagulant effects of warfarin; however, there are only rare reports of increased adverse risks of statins such as muscle-related toxicity.129
Several studies have demonstrated reduced warfa-rin dose requirements, increases in the international normalized ratio (INR), or changes in warfarin metabo-lite concentrations when coadministered with simvas-tatin.130–133 The magnitude of effect varies, but some reports indicate up to a 30% change in INR, and 1 re-port showed a doubling of the number of subjects with supratherapeutic INRs. This may be specific to genetic subgroups with low functioning CYP2C9. An analysis of >1100 patients indicated that simvastatin was as-sociated with a 29% reduced warfarin requirement in CYP2C9*3 carriers and very little change for noncar-riers.134 This may explain the varying magnitude of ef-fect in clinical studies.135 Case reports of INR changes after statin initiation have been published with fluvas-tatin,136–138 lovastatin,139 and rosuvastatin.140 One study indicated that lovastatin and simvastatin affected war-farin metabolite concentrations.131 There have been several investigations into a potential rosuvastatin-warfarin interaction. Two studies have shown a signifi-cant increase in INR, whereas 1 study did not.141–143 The mechanism of the rosuvastatin interaction is not completely established, although CYP2C9 seems a likely contributor. Several studies have demonstrated no interaction with warfarin for pitavastatin130,142 and atorvastatin.144 No clinically significant drug interac-
tions have been reported or are anticipated with statins and the novel anticoagulants dabigatran, apixaban, ri-varoxaban, and edoxaban.
Summary of Evidence for Statin-Warfarin DDIsThere is no clinically significant increase in statin expo-sure with coadministration of warfarin, and combination therapy is useful when clinically indicated.
Recommendations for Statin-Warfarin DDIs1. Use of a statin with warfarin as combination ther-
apy is useful when clinically indicated.2. The INR should be monitored more closely after
the initiation of a statin or a change in statin dose. The impact on the INR appears lowest for pitavas-tatin and atorvastatin.
ANTIPLATELET AGENTSTicagrelorTicagrelor is an oral, reversible, noncompetitive inhibitor of the platelet adenosine diphosphate receptor P2Y12 on the surface of platelets. It is currently approved for use in patients with acute coronary syndromes to reduce the risk of thrombotic cardiovascular events.145 Ticagrelor is rapidly absorbed and exhibits linear and predictable pharmacokinetics. The Cmax is reached in 1 to 4 hours after oral administration. The bioavailability of ticagre-lor is ≈36% with an elimination t1/2 of ≈7 hours for the parent drug and 9 hours for the active metabolite. Ti-cagrelor is metabolized predominantly by CYP3A4 and to a lesser extent by CYP3A5. Ticagrelor is also a P-gp substrate. In vitro metabolism studies demonstrate that ticagrelor and its active metabolite are weak inhibitors of CYP3A4 and P-gp.
Clinical trials have evaluated pharmacokinetic inter-actions with ticagrelor coadministered with either ator-vastatin 80 mg daily or simvastatin 80 mg daily. The atorvastatin-ticagrelor combination resulted in a 23% in-crease in the Cmax of atorvastatin and a 36% increase in the AUC. However, these changes were not statistically significant.146 The combination of simvastatin-ticagrelor resulted in a mean increase in Cmax of simvastatin of 81% and in the AUC of 56% (90% confidence interval, 1.30–1.87). Some subjects were observed to have greater increases in exposure to simvastatin with 2- to 3-fold increases in the Cmax and the AUC. The increases in Cmax and the AUC are likely attributable to inhibition of CYP3A4 by ticagrelor. Because of the reliance on CY-P3A4 of lovastatin for metabolism that is similar to that of simvastatin, it is likely that significant increases would also be expected with lovastatin. Of note, there were no clinically significant changes in the pharmacokinetic pa-
rameters of ticagrelor when coadministered with either of these agents. Despite the use of CYP3A4-metabolized statins in 90% of participants in the PLATO trial (Platelet Inhibition and Patient Outcomes), with simvastatin be-ing the predominantly used statin, these data cannot be used to assess clinically significant interactions between ticagrelor and CYP3A4-metabolized statins because concomitant therapy with simvastatin and lovastatin was restricted to a maximum of 40 mg daily. In addition, in-formation on the dose of statins used in patients receiv-ing ticagrelor was not routinely collected in the PLATO trial.147–149 No clinically significant drug interactions have been reported with the other P2Y12 inhibitors, prasugrel or clopidogrel, in combination with statins.
Summary of Evidence for Statin-Ticagrelor DDIsCoadministration of ticagrelor and atorvastatin results in only a minor increase in statin systemic exposure, and the combination is reasonable for appropriate patients. Combination therapy with ticagrelor and lovastatin or simvastatin may be considered.
Recommendations for Statin-Ticagrelor DDIs1. Coadministration of atorvastatin with ticagrelor
results in only a minor increase in statin systemic exposure and is reasonable for appropriate patients.
2. When prescribed in combination with ticagrelor, the dose of simvastatin and lovastatin should not exceed 40 mg daily.
3. There are no reports of significant interactions when ticagrelor is used in combination with pravas-tatin, fluvastatin, pitavastatin, or rosuvastatin, and no dosing restrictions are needed.
vASOPRESSIN RECEPTOR ANTAGONISTSConivaptanConivaptan is an intravenous dual vasopressin receptor (V1A and V2) antagonist that is currently approved to raise serum sodium in hospitalized patients with euvolemic and hypervolemic hyponatremia.150 Conivaptan is ex-tensively bound to plasma proteins and has an average elimination t1/2 of 5.3 hours. After intravenous adminis-tration, ≈83% of the dose is excreted in the feces and 12% in the urine.
Conivaptan is both a substrate and a potent inhibitor of CYP3A4. This isoenzyme has been identified as the sole cytochrome P450 isoenzyme responsible for me-tabolism of conivaptan. In clinical studies, conivaptan 30 mg daily resulted in a 3-fold increase in the AUC of simv-astatin as a result of decreased metabolism.150 In clinical trials with conivaptan, there have been 4 case reports of increased creatinine kinase/muscle-related toxicity and
2 cases of rhabdomyolysis in patients taking concomi-tant statin therapy. These cases involved simvastatin, lovastatin, and gemfibrozil/cerivastatin. No clinically sig-nificant interactions have been noted between the oral V2 receptor antagonist (tolvaptan) and lovastatin.151
The FDA-approved labeling states that the combina-tion of conivaptan with lovastatin or simvastatin should be avoided. Additionally, in patients currently receiving lovas-tatin or simvastatin, these agents should be held if under-going treatment with conivaptan. FDA labeling also states that lovastatin or simvastatin may be reinitiated at least 1 week after the infusion of conivaptan is completed.
Summary of Evidence for Statin-Conivaptan DDIsThe combination of conivaptan and lovastatin or simvas-tatin is potentially harmful and should be avoided. Atorv-astatin, pravastatin, fluvastatin, rosuvastatin, or pitavas-tatin may be considered in combination with conivaptan when clinically indicated.
Recommendations for Statin-vasopressin Receptor Antagonist DDIs
1. The combination of lovastatin or simvastatin with conivaptan is potentially harmful and should be avoided.
2. Atorvastatin, pravastatin, fluvastatin, rosuvastatin, or pitavastatin may be considered in combination with conivaptan when clinically indicated.
3. In the unlikely event of a need to use a statin while a patient is receiving conivaptan infusion, either atorvastatin or a statin that is not metabolized by CYP3A (pravastatin, fluvastatin, rosuvastatin, or pitavastatin) may be considered.
4. Tolvaptan may be used in combination with any statin at any approved doses.
IMMUNOSUPPRESSIvE AGENTSIn heart transplant recipients, statins are a cornerstone in immunosuppressant pharmacotherapy. The International Society of Heart and Lung Transplantation recommends the use of statins beginning 1 to 2 weeks after heart transplantation regardless of cholesterol concentrations because statins have been associated with a reduction in mortality, rejection associated with hemodynamic com-promise, and frequency and severity of coronary artery vasculopathy.152–155 Additionally, between 60% and 81% of heart transplant recipients exhibit lipid abnormalities.156,157 Although the majority of data in this population have been with simvastatin (5–20 mg daily) and pravastatin (20–40 mg daily), considerable controversy exists on which statin and what doses to use because of potential DDIs with the
calcineurin inhibitors (eg, cyclosporine and tacrolimus) that could lead to myopathy or rhabdomyolysis.153–156,158
CALCINEURIN INHIbITORSCyclosporine and TacrolimusCyclosporine and tacrolimus are extensively metabo-lized by hepatic and intestinal CYP3A4, act as both inhibitors and substrates of P-gp, and inhibit OAT-P1B1.22,159,160 As a result of their metabolism, both calcineurin inhibitors are predisposed to potential phar-macokinetic interactions with statins because atorv-astatin, simvastatin, and lovastatin are substrates of CYP3A4; atorvastatin, lovastatin, pravastatin, and simv-astatin are substrates of P-gp; and all current statins on the US market are substrates for OATP1B1.22 Simvas-tatin, lovastatin, atorvastatin, pravastatin, fluvastatin, pitavastatin, and rosuvastatin have been associated with 6- to 8-, 5- to 20-, 6- to 15-, 5- to 10-, 2- to 4-, 5-, and 7-fold increases in the AUC, respectively, when administered with cyclosporine.161 In addition, simvas-tatin, lovastatin, atorvastatin, and pravastatin have all been associated with rhabdomyolysis when used in combination with cyclosporine.162 FDA-approved prod-uct labeling recommends avoiding atorvastatin, lovas-tatin, pitavastatin, and simvastatin in combination with cyclosporine.24,26,29,30,163
More studies have reported DDIs with cyclosporine than with tacrolimus, in large part because of its earlier availability for clinical use. Because of the metabolism of tacrolimus, the patterns of statin DDIs would be ex-pected to be similar to those of cyclosporine.158 Unfortu-nately, limited data exist on tacrolimus and statin interac-tions. One open-label evaluation of 13 healthy volunteers suggested that after 4 days of therapy with atorvastatin 40 mg daily, 2 doses of tacrolimus had no impact on the atorvastatin pharmacokinetics.164
Target of Rapamycin InhibitorsSirolimus and everolimus are both macrolide immunosup-pressants that also have extensive hepatic and intestinal metabolism by CYP3A4 and P-gp.158 As with tacrolimus, extremely limited data exist on the interactions between target of rapamycin inhibitors and statins. Because of their metabolism, it is feasible that interactions with statins could occur and result in tissue injury. In case re-ports and case series, the use of sirolimus in combina-tion with statins has been associated with muscle-related toxicity, including rhabdomyolysis.165–167 Only 1 random-ized, open-label, 3-way crossover, single-dose study in 24 healthy volunteers has suggested that everolimus had no effect on the AUC of atorvastatin 20 mg or pravastatin 20 mg.168 Nonetheless, until further data exist, the panel sug-
gests that the dosing and choice of statin should follow the recommendations for the calcineurin inhibitors.
Summary of Evidence for Statin–Immunosuppressive Agent DDIsCombination therapy of cyclosporine, tacrolimus, evero-limus, or sirolimus with lovastatin, simvastatin, and pitavastatin is potentially harmful and should be avoided. The coadministration of tacrolimus and lovastatin, simv-astatin, or pitavastatin is potentially harmful and should be avoided. The combination of cyclosporine, everoli-mus, or sirolimus with rosuvastatin, atorvastatin, fluvas-tatin, or pravastatin may be considered.
Recommendations for Statin–Immunosuppressive Agent DDIs
1. Combination therapy of lovastatin, simvastatin, or pitavastatin with cyclosporine, everolimus, tacroli-mus, or sirolimus is potentially harmful and should be avoided.
2. The combination of rosuvastatin, atorvastatin, flu-vastatin, or pravastatin with cyclosporine, tacroli-mus, everolimus, or sirolimus may be considered.
3. The combination of cyclosporine, tacrolimus, everolimus, or sirolimus with daily doses of fluv-astatin, pravastatin, and rosuvastatin should be limited to 40, 20, and 5 mg daily, respectively.
4. The dose of atorvastatin >10 mg daily when coad-ministered with cyclosporine, tacrolimus, evero-limus, or sirolimus is not recommended without close monitoring of creatinine kinase and signs or symptoms of muscle-related toxicity.
MISCELLANEOUS AGENTSColchicineThere has been renewed interest in the anti-inflammatory properties of colchicine for the management of pericar-ditis and as a potential role in the prevention of cardio-vascular events.169
Interactions between colchicine and statins that un-dergo several different metabolic pathways have been described in the literature, suggesting that the underly-ing cause is likely multifactorial. Colchicine undergoes hepatic demethylation by CYP3A4. It does not appear to impair CYP3A4 activity; thus, the DDI between col-chicine and statins is likely attributable to competitive inhibition, which may result in increased concentrations of both substrates. Additionally, colchicine is a substrate for P-gp. Colchicine likely competes for P-gp–mediated efflux, resulting in accumulation of both substrates in myocytes and other target cells. Inhibition of P-gp by atorvastatin or lovastatin may further increase serum
colchicine concentrations.15 Colchicine does not appear to interact with OATP drug transporters. A pharmaco-dynamic mechanism may also be partially responsible for the effects observed clinically because myopathy is a well-described adverse effect of both colchicine and statin monotherapy. Evidence suggests that coadmin-istration of colchicine and statin therapy may produce synergistic muscle-related toxicity.
Statin-colchicine combination therapy has not been formally evaluated in clinical trials. It is unclear how spe-cific pharmacokinetic parameters may be affected. How-ever, clinically significant DDIs have been reported with atorvastatin, fluvastatin, lovastatin, pravastatin, and sim-vastatin when used in combination with colchicine.170–182 The DDI between colchicine and simvastatin is the most frequently reported in the literature, having been the subject of 6 cases. In each case, simvastatin-colchicine combination therapy resulted in myopathy, and 1 case progressed to rhabdomyolysis, multiorgan failure, and death.180 Rosuvastatin is not subject to pathways that interact with colchicine metabolism or disposition, and only limited data support a potential P-gp–mediated in-teraction with pitavastatin.19
The reported incidence of clinically meaningful inter-actions between colchicine and statin therapy may be deceptively low because both drugs share muscle-relat-ed adverse effects. A lack of awareness that colchicine can independently exert myotoxic effects (or be a con-tributor when coadministered with a statin) may lead cli-nicians to attribute any muscle-related findings to statin therapy alone. Although the incidence of muscle-related adverse effects was low when colchicine was added to statin therapy for the secondary prevention of cardiovas-cular events, the doses of colchicine used were much lower than those documented in case reports, suggest-ing that the DDI may be ameliorated in part by colchicine dose adjustment.169
Summary of Evidence for Statin-Colchicine DDIsCoadministration of colchicine and rosuvastatin, fluvas-tatin, lovastatin, pitavastatin, and pravastatin is reason-able when clinically indicated. Combination therapy with atorvastatin or simvastatin and colchicine may be con-sidered in appropriate patients.
Recommendations for Statin-Colchicine DDIs1. Coadministration of rosuvastatin, fluvastatin, lov-
astatin, pitavastatin, or pravastatin with colchicine is reasonable when clinically indicated.
2. Combination therapy with atorvastatin or simvas-tatin and colchicine may be considered in appropri-ate patients.
3. Patients receiving statin-colchicine combina-tion therapy should be monitored closely for
muscle-related signs and symptoms, given the potential for synergistic muscle-related toxicity.
4. Colchicine dose adjustments are recommended (loading doses of no more than 0.6–1.2 mg and maintenance doses of 0.3–0.6 mg daily) when used in conjunction with a CYP3A4 or P-gp inhibitor.
5. Dose reductions may be considered for atorvas-tatin, simvastatin, and lovastatin when coadmin-istered with colchicine, given the potential for interactions mediated by both CYP3A4 and P-gp pathways.
6. In patients with renal impairment, reduced doses of colchicine should be considered when used in combination with a statin.
HEART FAILURE MEDICATIONSIvabradineIvabradine is a specific inhibitor of the If current in the sinoatrial node. Unlike β-blockers, ivabradine does not modify myocardial contractility and intracardiac con-duction, even in patients with heart failure with reduced ejection fraction.183 In 2015, ivabradine was approved in the United States to reduce the risk of hospitaliza-tion for worsening heart failure in patients with stable, symptomatic, chronic heart failure with reduced ejec-tion fraction (ejection fraction ≤35%) who are in sinus rhythm with a resting heart rate ≥70 bpm and either are on maximally tolerated doses of β-blockers or have a contraindication to a β-blocker.184 Although ivabradine is extensively metabolized in the liver and intestines by CYP3A4-mediated oxidation, specific DDI studies have shown no clinically significant effect of ivabradine on the pharmacokinetics and pharmacodynamics of sim-vastatin.185 However, available pharmacokinetic and pharmacodynamic data on combination therapy with statins are limited at this time.
Sacubitril/valsartanSacubitril/valsartan is a combination of a neprilysin in-hibitor with the angiotensin receptor blocker valsartan. Approved in 2015 in the United States, sacubitril/val-sartan is indicated to reduce the risk of cardiovascular death and hospitalization for patients with heart failure with reduced ejection fraction (New York Heart Associa-tion class II–IV) and is typically used in combination with other heart failure therapies in place of an angiotensin receptor blocker or angiotensin-converting enzyme in-hibitor.186 Although CYP450 enzyme–mediated metabo-lism of sacubitril is minimal, in vitro data indicate that sacubitril inhibits OATP1B1, OATP1B3, OAT1, and OAT3 transporters. In a single phase III study, coadministration of sacubitril/valsartan with atorvastatin resulted in an in-creased Cmax of atorvastatin and its metabolites by up
to 2-fold and AUC by up to 1.3-fold; however, no signifi-cant adverse events related to atorvastatin were report-ed.187 No dose adjustments are currently proposed for atorvastatin or other statins when coadministered with sacubitril/valsartan in US package labeling.188 However, further pharmacokinetic studies are needed to fully ad-dress statin interactions.
Summary of Evidence for Statin–Heart Failure Medication DDIsCurrent data suggest no safety concerns when ivabradine is combined with a statin. In vitro studies indicate that sa-cubitril/valsartan has the potential to interact with statins that are substrates of OATP1B1, OATP1B3, OAT1, and OAT3.188 However, the clinical significance of these po-tential interactions is unknown.
Recommendations for Statin–Heart Failure Medication DDIs
1. Coadministration of a statin at an approved dose with ivabridine is reasonable when clinically indicated.
2. Lower doses of atorvastatin, fluvastatin, pitavas-tatin, pravastatin, rosuvastatin, or simvastatin may be considered when used in combination with sacubitril/valsartan.
CONCLUSIONSStatin medications are commonly prescribed to reduce morbidity and mortality in patients with and at risk for ASCVD events. Statin DDIs in cardiovascular patients are often unavoidable and should be clinically managed. Healthcare providers should be knowledgeable about the dose limits, adverse effects, and monitoring parameters associated with these DDIs to minimize toxicity. A review of all medications that statin-treated patients are taking should be done at each clinical encounter and during tran-sitions of care within a health system so that DDIs can be identified early, evaluated, and managed appropriately by implementing doses adjustments, changing to a safer statin medication, or discontinuing when needed. A thor-ough understanding of the pharmacokinetics of statins and other select medications that are often prescribed in combination is paramount in ensuring patient safety. Additional medications not reviewed here but of great
importance are the agents used to treat HIV. A review of these drug interactions is beyond the scope of this document. However, because of the extent of these in-teractions, particularly with statins, the reader is referred elsewhere189 to assist with this patient population.
FOOTNOTESThe American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifical-ly, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such rela-tionships that might be perceived as real or potential conflicts of interest.
This statement was approved by the American Heart Asso-ciation Science Advisory and Coordinating Committee on May 6, 2016, and the American Heart Association Executive Com-mittee on June 8, 2016. A copy of the document is available at http://professional.heart.org/statements by using either “Search for Guidelines & Statements” or the “Browse by Topic” area. To purchase additional reprints, call 843-216-2533 or e-mail [email protected].
The American Heart Association requests that this docu-ment be cited as follows: Wiggins BS, Saseen JJ, Page RL 2nd, Reed BN, Sneed K, Kostis JB, Lanfear D, Virani S, Mor-ris PB; on behalf of the American Heart Association Clinical Pharmacology Committee of the Council on Clinical Cardi-ology; Council on Hypertension; Council on Quality of Care and Outcomes Research; and Council on Functional Genom-ics and Translational Biology. Recommendations for man-agement of clinically significant drug-drug interactions with statins and select agents used in patients with cardiovascu-lar disease: a scientific statement from the American Heart Association. Circulation. 2016;134:XXX–XXX. doi: 10.1161/CIR.0000000000000456.
Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA state-ments and guidelines development, visit http://professional. heart.org/statements. Select the “Guidelines & Statements” drop-down menu, then click “Publication Development.”
Permissions: Multiple copies, modification, alteration, enhance-ment, and/or distribution of this document are not permitted with-out the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright-Permission-Guidelines_UCM_300404_Article.jsp. A link to the “Copyright Permissions Request Form” appears on the right side of the page.
Circulation is available at http://circ.ahajournals.org.
Barbara S. Wiggins Medical University of South Carolina
None None None None None None None
Joseph J. Saseen University of Colorado Anschutz Medical Campus
None None None None None None None
John B. Kostis Rutgers University/Robert Wood Johnson Medical School
Pfizer† None None None None None None
David Lanfear Henry Ford Hospital Novartis†; Janssen†; Amgen†
None None None None None None
Pamela B. Morris Medical University of South Carolina None None None None None AstraZeneca*; Amgen*; Sanofi
Regeneron*
None
Robert L. Page II University of Colorado Anschutz Medical Campus
None None None None None None None
Brent N. Reed University of Maryland School of Pharmacy
None None None None None None None
Kevin Sneed University of South Florida College of Pharmacy
None None None None None None None
Salim Virani Baylor College of Medicine/Michael E. DeBakey VA Medical Center
None None None None None None None
This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10 000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.
*Modest.†Significant.
DISCLOSURES
Reviewer Disclosures
Reviewer Employment Research Grant
Other Research Support
Speakers’ bureau/
HonorariaExpert
WitnessOwnership
Interest
Consultant/Advisory
board Other
Martin Bergmann
Asklepios Klinik St. Georg (Germany)
None None None None None None None
Dominique Deplanque
University Lille North of France (France)
None None None None None None None
Alexander Kulik
Boca Raton Regional Hospital
Pfizer (research grant to help support an atorvastatin
post-CABG clinical trial)*; AstraZeneca (research grant to help support a ticagrelor post-
BH. Potential determinants of drug-drug interaction associated dispensing in community pharmacies. Drug Saf. 2005;28:371–378.
3. Shapiro LE, Shear NH. Drug-drug interactions: how scared should we be? CMAJ. 1999;161:1266–1267.
4. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389.
5. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average choles-terol levels: Cholesterol and Recurrent Events Trial investiga-tors. N Engl J Med. 1996;335:1001–1009. doi: 10.1056/NEJM199610033351401.
6. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels: the Long-Term Intervention and Pravas-tatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349–1357. doi: 10.1056/NEJM199811053391902.
7. Heart Protection Study Collaborative Group. MRC/BHF Heart Pro-tection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lan-cet. 2002;360:7–22. doi: 10.1016/S0140-6736(02)09327-3.
8. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr. Primary preven-tion of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615–1622.
9. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J; ASCOT Investigators. Pre-vention of coronary and stroke events with atorvastatin in hyper-tensive patients who have average or lower-than-average choles-terol concentrations, in the Anglo-Scandinavian Cardiac Outcomes
Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149–1158. doi: 10.1016/S0140-6736(03)12948-0.
10. Stone N, Robinson J, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic risk in adults: a report of the Ameri-can College of Cardiology/American Heart Association Task Force on Practice Guidelines [published corrections appear in Circulation. 2014;129[suppl 2]:S46-S48 and Circulation. 2015;132:e396]. Circulation. 2014;129(suppl 2):S1–S45. doi: 10.1161/01.cir.0000437738.63853.7a.
11. Nebert DW, Russell DW. Clinical importance of the cy-tochromes P450. Lancet. 2002;360:1155–1162. doi: 10.1016/S0140-6736(02)11203-7.
12. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352:2211–2221. doi: 10.1056/NEJMra032424.
13. Bullman J, Nicholls A, Van Landingham K, Fleck R, Vuong A, Miller J, Alexander S, Messenheimer J. Effects of la-motrigine and phenytoin on the pharmacokinetics of atorvas-tatin in healthy volunteers. Epilepsia. 2011;52:1351–1358. doi: 10.1111/j.1528-1167.2011.03118.x.
14. Dingemanse J, Schaarschmidt D, van Giersbergen PL. In-vestigation of the mutual pharmacokinetic interactions be-tween bosentan, a dual endothelin receptor antagonist, and simvastatin. Clin Pharmacokinet. 2003;42:293–301. doi: 10.2165/00003088-200342030-00004.
15. Bogman K, Peyer AK, Török M, Küsters E, Drewe J. HMG-CoA re-ductase inhibitors and P-glycoprotein modulation. Br J Pharmacol. 2001;132:1183–1192. doi: 10.1038/sj.bjp.0703920.
16. Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug inter-actions with HMG-CoA reductase inhibitors. Clin Pharmacokinet. 2002;41:343–370. doi: 10.2165/00003088-200241050-00003.
17. Hochman JH, Pudvah N, Qiu J, Yamazaki M, Tang C, Lin JH, Prueksaritanont T. Interactions of human P-glycoprotein with
Gregory Schwartz
Veterans Affairs Medical Center and
University of Colorado School of Medicine
Sanofi (research grant to institution)*; Resverlogox
(research grant to institution)*; Medicines Company (research
grant to institution)*; Roche (research grant to institution)*;
Cerenis (research grant to institution)*
None None None None None None
This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10 000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.
simvastatin, simvastatin acid, and atorvastatin. Pharm Res. 2004;21:1686–1691.
18. Wang E, Casciano CN, Clement RP, Johnson WW. HMG-CoA re-ductase inhibitors (statins) characterized as direct inhibitors of P-glycoprotein. Pharm Res. 2001;18:800–806.
19. Fujino H, Saito T, Ogawa S, Kojima J. Transporter-mediated influx and efflux mechanisms of pitavastatin, a new inhibitor of HMG-CoA reductase. J Pharm Pharmacol. 2005;57:1305–1311. doi: 10.1211/jpp.57.10.0009.
20. Wessler JD, Grip LT, Mendell J, Giugliano RP. The P-glycoprotein transport system and cardiovascular drugs [published cor-rection appears in J Am Coll Cardiol. 2014;63:2176]. J Am Coll Cardiol. 2013;61:2495–2502. doi: 10.1016/j.jacc.2013. 02.058.
21. US Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors, and inducers. http://www.fda.gov/drugs/developmentapprovalprocess/development resources/druginteractionslabeling/ucm093664.htm. Accessed August 7, 2014.
22. Kalliokoski A, Niemi M. Impact of OATP transporters on phar-macokinetics. Br J Pharmacol. 2009;158:693–705. doi: 10.1111/j.1476-5381.2009.00430.x.
23. Hua WJ, Hua WX, Fang HJ. The role of OATP1B1 and BCRP in pharmacokinetics and DDI of novel statins. Cardiovasc Ther. 2012;30:e234–e241. doi: 10.1111/j.1755-5922.2011.00290.x.
24. Atorvastatin (Lipitor) [package insert]. New York, NY: Pfizer; 2013.
31. Igel M, Sudhop T, von Bergmann K. Metabolism and drug interac-tions of 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibi-tors (statins). Eur J Clin Pharmacol. 2001;57:357–364.
32. Kajinami K, Takekoshi N, Saito Y. Pitavastatin: efficacy and safety profiles of a novel synthetic HMG-CoA reductase inhibitor. Cardio-vasc Drug Rev. 2003;21:199–215.
33. Rodriques AD. Prioritization of clinical drug interaction stud-ies using in vitro cytochrome P450 data: proposed refine-ment and expansion of the “rank order” approach. Drug Metab Lett.2007;1:31–35.
34. Farnier M. Safety review of combination drugs for hyper-lipidemia. Expert Opin Drug Saf. 2011;10:363–371. doi: 10.1517/14740338.2011.540237.
35. Shitara Y, Hirano M, Sato H, Sugiyama Y. Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction be-tween cerivastatin and gemfibrozil. J Pharmacol Exp Ther. 2004;311:228–236. doi: 10.1124/jpet.104.068536.
36. Paragh G, Balogh Z, Romics L. Antilipemic therapy and rhabdomy-olysis [in Hungarian]. Orv Hetil. 2003;144:515–520.
37. Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Gre-nade L, Gurwitz JH, Chan KA, Goodman MJ, Platt R. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA. 2004;292:2585–2590. doi: 10.1001/jama.292.21.2585.
38. Chang JT, Staffa JA, Parks M, Green L. Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy. Pharmacoepidemiol Drug Saf. 2004;13:417–426. doi: 10.1002/pds.977.
39. Layne RD, Sehbai AS, Stark LJ. Rhabdomyolysis and renal fail-ure associated with gemfibrozil monotherapy. Ann Pharmacother. 2004;38:232–234. doi: 10.1345/aph.1D282.
40. Gaist D, Rodríguez LA, Huerta C, Hallas J, Sindrup SH. Lipid-low-ering drugs and risk of myopathy: a population-based follow-up study. Epidemiology. 2001;12:565–569.
41. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin. Am J Cardiol. 2005;95:120–122. doi: 10.1016/j.amjcard.2004.08.076.
42. Amend KL, Landon J, Thyagarajan V, Niemcryk S, McAfee A. Inci-dence of hospitalized rhabdomyolysis with statin and fibrate use in an insured US population. Ann Pharmacother. 2011;45:1230–1239. doi: 10.1345/aph.1Q110.
43. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart dis-ease in men with low levels of high-density lipoprotein cholesterol: Veterans Affairs High-Density Lipoprotein Cholesterol Interven-tion Trial Study Group. N Engl J Med. 1999;341:410–418. doi: 10.1056/NEJM199908053410604.
44. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Mäenpää H, Mälkönen M, Mänttäri M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjöblom T, Nikkilä EA. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipid-emia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237–1245. doi: 10.1056/NEJM198711123172001.
45. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA. 1990;264:71–75.
46. Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety con-siderations with fibrate therapy. Am J Cardiol. 2007;99(suppl): 3C–18C.
47. Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with fibrates. Am J Cardiol. 2004;94:935–938. doi: 10.1016/ j.amjcard.2004.06.033.
48. Bottorff MB. Statin safety and drug interactions: clinical im-plications. Am J Cardiol. 2006;97:27C–31C. doi: 10.1016/ j.amjcard.2005.12.007.
49. Lopid (gemfibrozil) tablets [package insert]. New York, NY: Parke-Davis; revised 2010.
50. Ogilvie BW, Zhang D, Li W, Rodrigues AD, Gipson AE, Holsapple J, Toren P, Parkinson A. Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions. Drug Metab Dispos. 2006;34:191–197. doi: 10.1124/dmd.105.007633.
51. Okerholm RA, Keeley FJ, Peterson FE, Glazko AJ. The metabolism of gemfibrozil. Proc R Soc Med. 1976;69(suppl 2):11–14.
52. Elsby R, Hilgendorf C, Fenner K. Understanding the critical dis-position pathways of statins to assess drug-drug interaction risk during drug development: it’s not just about OATP1B1. Clin Phar-macol Ther. 2012;92:584–598. doi: 10.1038/clpt.2012.163.
53. Goosen TC, Bauman JN, Davis JA, Yu C, Hurst SI, Williams JA, Loi CM. Atorvastatin glucuronidation is minimally and nonselectively inhibited by the fibrates gemfibrozil, fenofibrate, and fenofibric acid. Drug Metab Dispos. 2007;35:1315–1324. doi: 10.1124/dmd.107.015230.
54. Backman JT, Kyrklund C, Kivistö KT, Wang JS, Neuvonen PJ. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther. 2000;68:122–129. doi: 10.1067/mcp.2000.108507.
55. Kyrklund C, Backman JT, Kivistö KT, Neuvonen M, Laitila J, Neu-vonen PJ. Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin Pharmacol Ther. 2001;69:340–345.
56. Whitfield LR, Porcari AR, Alvey C, Abel R, Bullen W, Hartman D. Effect of gemfibrozil and fenofibrate on the pharmacokinet-ics of atorvastatin. J Clin Pharmacol. 2011;51:378–388. doi: 10.1177/0091270010366446.
57. Backman JT, Luurila H, Neuvonen M, Neuvonen PJ. Rifampin mark-edly decreases and gemfibrozil increases the plasma concentra-tions of atorvastatin and its metabolites. Clin Pharmacol Ther. 2005;78:154–167. doi: 10.1016/j.clpt.2005.04.007.
59. Schneck DW, Birmingham BK, Zalikowski JA, Mitchell PD, Wang Y, Martin PD, Lasseter KC, Brown CD, Windass AS, Raza A. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther. 2004;75:455–463.
60. Bergman E, Matsson EM, Hedeland M, Bondesson U, Knut-son L, Lennernäs H. Effect of a single gemfibrozil dose on the pharmacokinetics of rosuvastatin in bile and plasma in healthy volunteers. J Clin Pharmacol. 2010;50:1039–1049. doi: 10.1177/0091270009357432.
61. Mathew P, Cuddy T, Tracewell WG, Salazar D. An open-label study on the pharmacokinetics (PK) of pitavastatin (NK-104) when ad-ministered concomitantly with fenofibrate or gemfibrozil in healthy volunteers. Clin Pharmacol Ther. 2004;75:33.
62. Noé J, Portmann R, Brun ME, Funk C. Substrate-dependent drug-drug interactions between gemfibrozil, fluvastatin and other or-ganic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. Drug Metab Dispos. 2007;35:1308–1314. doi: 10.1124/dmd.106.012930.
63. Spence JD, Munoz CE, Hendricks L, Latchinian L, Khouri HE. Phar-macokinetics of the combination of fluvastatin and gemfibrozil. Am J Cardiol. 1995;76:80A–83A.
64. Settergren J, Eiermann B, Mannheimer B. Adherence to drug label recommendations for avoiding drug interactions causing statin-induced myopathy: a nationwide register study. PLoS One. 2013;8:e69545. doi: 10.1371/journal.pone.0069545.
65. Abbvie Inc. TRICOR (fenofibrate) tablets [package insert]. http://www.rxabbvie.com/pdf/tricorpi.pdf. Accessed June 7, 2014.
66. Abbvie Inc. TRILIPIX (fenofibric acid) capsules [package insert]. http://www.rxabbvie.com/pdf/trilipix_pi.pdf. Accessed June 7, 2014.
67. Gupta R, Birnbaum Y, Uretsky BF. The renal patient with coro-nary artery disease: current concepts and dilemmas [published correction appears in J Am Coll Cardiol. 2004;44:2283]. J Am Coll Cardiol. 2004;44:1343–1353. doi: 10.1016/j.jacc.2004.06.058.
68. Prueksaritanont T, Tang C, Qiu Y, Mu L, Subramanian R, Lin JH. Ef-fects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos. 2002;30:1280–1287.
69. Pan WJ, Gustavson LE, Achari R, Rieser MJ, Ye X, Gutterman C, Wallin BA. Lack of a clinically significant pharmacokinetic interac-tion between fenofibrate and pravastatin in healthy volunteers. J Clin Pharmacol. 2000;40:316–323.
70. Martin PD, Dane AL, Schneck DW, Warwick MJ. An open-label, randomized, three-way crossover trial of the effects of coadmin-istration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male vol-unteers. Clin Ther. 2003;25:459–471.
71. Zhu T, Awni WM, Hosmane B, Kelly MT, Sleep DJ, Stolzenbach JC, Wan K, Chira TO, Pradhan RS. ABT-335, the choline salt of fenofibric acid, does not have a clinically significant pharmaco-kinetic interaction with rosuvastatin in humans. J Clin Pharmacol. 2009;49:63–71. doi: 10.1177/0091270008325671.
72. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesäniemi YA, Sullivan D, Hunt D, Colman P, d’Emden M, Whiting M, Ehnholm C, Laakso M; FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): ran-domised controlled trial [published correction appears in Lan-cet. 2006;368:1420]. Lancet. 2005;366:1849–1861. doi: 10.1016/S0140-6736(05)67667-2.
73. Accord Study Group, Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC Jr, Cushman WC, Simons-Morton DG, Byington RP. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–1574. doi: 10.1056/NEJMoa1001282.
74. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy [published correction appears in N Engl J Med. 2012;367:189]. N Engl J Med. 2011;365:2255–2267. doi: 10.1056/NEJMoa1107579.
75. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER nia-cin/laropiprant: trial design, pre-specified muscle and liver out-comes, and reasons for stopping study treatment. Eur Heart J. 2013;34:1279–1291. doi:10.1093/eurheartj/eht55.
77. Kaski JC, Aldama G, Cosín-Sales J. Cardiac syndrome X: diag-nosis, pathogenesis and management. Am J Cardiovasc Drugs. 2004;4:179–194.
78. Romero M, Sánchez I, Pujol MD. New advances in the field of calcium channel antagonists: cardiovascular effects and struc-ture-activity relationships. Curr Med Chem Cardiovasc Hematol Agents. 2003;1:113–141.
79. Molden E, Skovlund E, Braathen P. Risk management of simvas-tatin or atorvastatin interactions with CYP3A4 inhibitors. Drug Saf. 2008;31:587–596.
80. Neuvonen PJ, Backman JT, Niemi M. Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, flu-vastatin and pravastatin. Clin Pharmacokinet. 2008;47:463–474. doi: 10.2165/00003088-200847070-00003.
81. Rifkin SI. Multiple drug interactions in a renal transplant patient leading to simvastatin-induced rhabdomyolysis: a case report. Medscape J Med. 2008;10:264.
82. You JH, Chan WK, Chung PF, Hu M, Tomlinson B. Effects of con-comitant therapy with diltiazem on the lipid responses to simvas-tatin in Chinese subjects. J Clin Pharmacol. 2010;50:1151–1158. doi: 10.1177/0091270009358082.
83. Hu M, Mak VW, Tomlinson B. Simvastatin-induced myopathy, the role of interaction with diltiazem and genetic predisposi-tion. J Clin Pharm Ther. 2011;36:419–425. doi: 10.1111/ j.1365-2710.2010.01184.x.
84. Mousa O, Brater DC, Sunblad KJ, Hall SD. The interaction of diltia-zem with simvastatin. Clin Pharmacol Ther. 2000;67:267–274. doi: 10.1067/mcp.2000.104609.
85. Azie MD, Brater DC, Becker PA,Jones DR, Hall SD. The interaction of diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther. 1998;64:369–377.
86. Lewin JJ 3rd, Nappi JM, Taylor MH. Rhabdomyolysis with concurrent atorvastatin and diltiazem. Ann Pharmacother. 2002;36:1546–1549.
87. Choi DH, Li C, Choi JS. Effects of simvastatin on the pharmacoki-netics of verapamil and its main metabolite, norverapamil, in rats. Eur J Drug Metab Pharmacokinet. 2009;34:163–168.
88. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hyper-tensive patients randomized to angiotensin-converting enzyme in-hibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [published corrections appear in JAMA. 2003;289:178 and JAMA. 2004;291:2196]. JAMA. 2002;288:2981–2997.
89. Amlodipine [package insert]. New York, NY: Pfizer Labs; 2011. 90. Diltiazem [package insert]. Macquarie Park, NSW: Sanofi-Aventis,
Australia Pty Ltd; 2014. 91. Verapamil [package insert]. New York, NY: Pfizer Labs; 2011. 92. Alsheikh-Ali AA, Karas RH. Adverse events with concomitant ami-
odarone and statin therapy. Prev Cardiol. 2005;8:95–97. 93. Pfizer Inc. CORDARONE (amiodarone HCL) tablets. http://
labeling.pfizer.com/showlabeling.aspx?id=93. Accessed June 9, 2014.
94. Sanofi-Aventis US LLC. MULTAQ (dronedarone) tablets. http://www.multaq.com/docs/consumer_pdf/pi.aspx. Accessed June 22, 2014.
95. Wratchford P, Ponte CD. High-dose simvastatin and rhabdomyoly-sis. Am J Health Syst Pharm. 2003;60:698–700.
96. de Denus S, Spinler SA. Amiodarone’s role in simvastatin-associ-ated rhabdomyolysis. Am J Health Syst Pharm. 2003;60:1791; author reply 1791–1792.
97. Roten L, Schoenenberger RA, Krähenbühl S, Schlienger RG. Rhabdomyolysis in association with simvastatin and amio-darone. Ann Pharmacother. 2004;38:978–981. doi: 10.1345/aph.1D498.
98. Saliba WR, Elias M. Myopathy from the combination of simv-astatin and amiodarone. Eur J Intern Med. 2006;17:148. doi: 10.1016/j.ejim.2005.09.018.
99. Ricaurte B, Guirguis A, Taylor HC, Zabriskie D. Simvastatin-amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity. Ann Pharmacother. 2006;40:753–757. doi: 10.1345/aph.1G462.
100. Marot A, Morelle J, Chouinard VA, Jadoul M, Lambert M, Demoulin N. Concomitant use of simvastatin and amiodarone resulting in severe rhabdomyolysis: a case report and review of the literature. Acta Clin Belg. 2011;66:134–136. doi: 10.2143/ACB.66.2.20625533.
101. Merz T, Fuller SH. Elevated serum transaminase levels resulting from concomitant use of rosuvastatin and amiodarone. Am J Health Syst Pharm. 2007;64:1818–1821. doi: 10.2146/ajhp060305.
102. Chouhan UM, Chakrabarti S, Millward LJ. Simvastatin interac-tion with clarithromycin and amiodarone causing myositis. Ann Pharmacother. 2005;39:1760–1761. doi: 10.1345/aph.1G195.
103. Becquemont L, Neuvonen M, Verstuyft C, Jaillon P, Letierce A, Neuvonen PJ, Funck-Brentano C. Amiodarone interacts with simvastatin but not with pravastatin disposition kinet-ics. Clin Pharmacol Ther. 2007;81:679–684. doi: 10.1038/sj.clpt.6100098.
104. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage J, Bowman L, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, Parish S, Peto R, Collins R. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind ran-domised trial. Lancet. 2010;376:1658–1669. doi: 10.1016/S0140-6736(10)60310-8.
105. Burkart F, Pfisterer M, Kiowski W, Follath F, Burckhardt D. Effect of antiarrhythmic therapy on mortality in survivors of myocardial infarction with asymptomatic complex ventricular arrhythmias: Basel Antiarrhythmic Study of Infarct Survival (BASIS). J Am Coll Cardiol. 1990;16:1711–1718.
106. Cairns JA, Connolly SJ, Roberts R, Gent M. Randomised trial of outcome after myocardial infarction in patients with
frequent or repetitive ventricular premature depolarisations: CAMIAT: Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators [published correction appears in Lancet. 1997;349:1776]. Lancet. 1997;349:675–682.
107. Doval HC, Nul DR, Grancelli HO, Perrone SV, Bortman GR, Curiel R. Randomised trial of low-dose amiodarone in severe congestive heart failure: Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA). Lancet. 1994;344:493–498.
108. Julian DG, Camm AJ, Frangin G, Janse MJ, Munoz A, Schwartz PJ, Simon P. Randomised trial of effect of amiodarone on mor-tality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT: European Myocardial Infarct Amiodarone Trial Investigators [published corrections appear in Lancet. 1997;349:1180 and Lancet. 1997;349:1776]. Lancet. 1997;349:667–674.
109. A comparison of antiarrhythmic-drug therapy with implantable de-fibrillators in patients resuscitated from near-fatal ventricular ar-rhythmias: the Antiarrhythmics Versus Implantable Defibrillators (AVID) Investigators. N Engl J Med. 1997;337:1576–1583. doi: 10.1056/NEJM199711273372202.
110. Borders-Hemphill V. Concurrent use of statins and amiodarone. Consult Pharm. 2009;24:372–379.
111. Karimi S, Hough A, Beckey C, Parra D. Results of a safety initia-tive for patients on concomitant amiodarone and simvastatin ther-apy in a Veterans Affairs medical center. J Manag Care Pharm. 2010;16:472–481. doi: 10.18553/jmcp.2010.16.7.472.
112. Zhelyazkova-Savova M, Gancheva S, Sirakova V. Potential statin-drug interactions: prevalence and clinical significance. Springerplus. 2014;3:168. doi: 10.1186/2193-1801-3-168.
113. Dale KM, White CM. Dronedarone: an amiodarone analog for the treatment of atrial fibrillation and atrial flutter. Ann Pharmacother. 2007;41:599–605. doi: 10.1345/aph.1H524.
114. Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, Connolly SJ; ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fi-brillation [published correction appears in N Engl J Med. 2009;360:2487]. N Engl J Med. 2009;360:668–678. doi: 10.1056/NEJMoa0803778.
115. Singh BN, Connolly SJ, Crijns HJ, Roy D, Kowey PR, Capucci A, Radzik D, Aliot EM, Hohnloser SH; EURIDIS and ADONIS Investigators. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357:987–999. doi: 10.1056/NEJMoa054686.
116. Le Heuzey JY, De Ferrari GM, Radzik D, Santini M, Zhu J, Davy JM. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amio-darone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol. 2010;21:597–605. doi: 10.1111/j.1540-8167.2010.01764.x.
117. Digoxin [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2009. http://www.accessdata.fda.gov/drug-satfda_docs/label/2010/009330s025lbl.pdf. Accessed August 28, 2016.
118. Boyd RA, Stern RH, Stewart BH, Wu X, Reyner EL, Zegarac EA, Randinitis EJ, Whitfield L. Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion. J Clin Pharmacol. 2000;40: 91–98.
119. Jerling M. Clinical pharmacokinetics of ranolazine. Clin Pharmacokinet. 2006;45:469–491. doi: 10.2165/00003088- 200645050-00003.
120. Jerling M, Huan BL, Leung K, Chu N, Abdallah H, Hussein Z. Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects. J Clin Pharmacol. 2005;45:422–433. doi: 10.1177/0091270004273992.
121. Hylton AC, Ezekiel TO. Rhabdomyolysis in a patient receiving rano-lazine and simvastatin. Am J Health Syst Pharm. 2010;67:1829–1831. doi: 10.2146/ajhp090299.
122. Correa D, Landau M. Ranolazine-induced myopathy in a patient on chronic statin therapy. J Clin Neuromuscul Dis. 2013;14:114–116. doi: 10.1097/CND.0b013e31828525a5.
123. Ginanneschi F, Volpi N, Giannini F, Rocchi R, Donati D, Aglianò M, Lorenzoni P, Rossi A. Rhabdomyolysis in an elderly multitreated patient: multiple drug interactions after statin withdrawal. J Neurol Sci. 2014;336:284–287. doi: 10.1016/j.jns.2013.10.040.
124. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, Murphy SA, Budaj A, Varshavsky S, Wolff AA, Skene A, McCabe CH, Braunwald E; MERLIN-TIMI 36 Trial Investigators. Effects of ra-nolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA. 2007;297:1775–1783. doi: 10.1001/jama.297.16.1775.
125. Kosiborod M, Arnold SV, Spertus JA, McGuire DK, Li Y, Yue P, Ben-Yehuda O, Katz A, Jones PG, Olmsted A, Belardinelli L, Chaitman BR. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA ran-domized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina). J Am Coll Cardiol. 2013;61:2038–2045. doi: 10.1016/j.jacc.2013.02.011.
126. Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W, Skettino SL, Wolff AA; Combination Assessment of Ranolazine In Stable Angina (CARISA) Investigators. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tol-erance and angina frequency in patients with severe chronic an-gina: a randomized controlled trial. JAMA. 2004;291:309–316. doi: 10.1001/jama.291.3.309.
127. Ranolazine [package insert]. Foster City, CA; Gilead Sciences, Inc. January 2016.
128. Kellick KA, Bottorff M, Toth PP, National Lipid Association’s Safety Task Force. A clinician’s guide to statin drug-drug inter-actions. J Clin Lipidol. 2014;8(suppl):S30–S46. doi: 10.1016/j.jacl.2014.02.010.
129. Mackay JW, Fenech ME, Myint KS. Acute rhabdomyolysis caused by combination therapy with atorvastatin and warfarin. Br J Hosp Med (Lond). 2012;73:106–107.
130. Hickmott H, Wynne H, Kamali F. The effect of simvastatin co-med-ication on warfarin anticoagulation response and dose require-ments. Thromb Haemost. 2003;89:949–950. doi: 10.1267/THRO03050949.
131. Herman D, Locatelli I, Grabnar I, Peternel P, Stegnar M, Lainscak M, Mrhar A, Breskvar K, Dolzan V. The influence of co-treat-ment with carbamazepine, amiodarone and statins on warfa-rin metabolism and maintenance dose. Eur J Clin Pharmacol. 2006;62:291–296. doi: 10.1007/s00228-006-0104-4.
132. Lin JC, Ito MK, Stolley SN, Morreale AP, Marcus DB. The effect of converting from pravastatin to simvastatin on the pharmacody-namics of warfarin. J Clin Pharmacol. 1999;39:86–90.
133. Sconce EA, Khan TI, Daly AK, Wynne HA, Kamali F. The im-pact of simvastatin on warfarin disposition and dose re-quirements. J Thromb Haemost. 2006;4:1422–1424. doi: 10.1111/j.1538-7836.2006.01974.x.
134. Andersson ML, Eliasson E, Lindh JD. A clinically significant inter-action between warfarin and simvastatin is unique to carriers of the CYP2C9*3 allele. Pharmacogenomics. 2012;13:757–762. doi: 10.2217/pgs.12.40.
135. Westergren T, Johansson P, Molden E. Probable warfarin-simvas-tatin interaction. Ann Pharmacother. 2007;41:1292–1295. doi: 10.1345/aph.1K167.
136. Kline SS, Harrell CC. Potential warfarin-fluvastatin interaction. Ann Pharmacother. 1997;31:790.
137. Trilli LE, Kelley CL, Aspinall SL, Kroner BA. Potential interac-tion between warfarin and fluvastatin. Ann Pharmacother. 1996;30:1399–1402.
138. Andrus MR. Oral anticoagulant drug interactions with statins: case report of fluvastatin and review of the literature. Pharmacotherapy. 2004;24:285–290.
139. Ahmad S. Lovastatin: warfarin interaction. Arch Intern Med. 1990;150:2407.
140. Barry M. Rosuvastatin-warfarin drug interaction. Lancet. 2004;363:328. doi: 10.1016/S0140-6736(03)15396-2.
141. Simonson SG, Martin PD, Mitchell PD, Lasseter K, Gibson G, Schneck DW. Effect of rosuvastatin on warfarin pharmacodynam-ics and pharmacokinetics. J Clin Pharmacol. 2005;45:927–934. doi: 10.1177/0091270005278224.
142. Yu CY, Campbell SE, Zhu B, Knadler MP, Small DS, Sponseller CA, Hunt TL, Morgan RE. Effect of pitavastatin vs. rosuvastatin on international normalized ratio in healthy volunteers on steady-state warfarin. Curr Med Res Opin. 2012;28:187–194. doi: 10.1185/03007995.2011.648264.
143. Jindal D, Tandon M, Sharma S, Pillai KK. Pharmacodynamic evaluation of warfarin and rosuvastatin co-administration in healthy subjects. Eur J Clin Pharmacol. 2005;61:621–625. doi: 10.1007/s00228-005-0986-6.
144. Stern R, Abel R, Gibson GL, Besserer J. Atorvastatin does not alter the anticoagulant activity of warfarin. J Clin Pharmacol. 1997;37:1062–1064.
146. Teng R, Mitchell PD, Butler KA. Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers. Eur J Clin Pharmacol. 2013;69:477–487. doi: 10.1007/s00228-012-1369-4.
147. Dinicolantonio JJ, Serebruany VL. Exploring the ticagrelor-statin interplay in the PLATO trial. Cardiology. 2013;124:105–107. doi: 10.1159/000346151.
148. US Food and Drug Administration. Drug approval package. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/ 022433Orig1s000TOC.cfm. Accessed October 23, 2014.
149. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators,Freij A, Thorsén M;. Ticagrelor versus clopido-grel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. doi: 10.1056/NEJMoa0904327.
150. Astellas Pharma US, Inc. Conivaptan [package insert]. http://www.astellas.us/docs/vaprisol.pdf. Accessed May 10, 2014.
151. Otsuka. Tolvaptan [package insert]. http://www.otsuka-us.com/products/Documents/Samsca.PI.pdf. Accessed August 28, 2016.
152. Costanzo MR, Dipchand A, Starling R, Anderson A, Chan M, Desai S, Fedson S, Fisher P, Gonzales-Stawinski G, Martinelli L, McGiffin D, Smith J, Taylor D, Meiser B, Webber S, Baran D, Carboni M, Dengler T, Feldman D, Frigerio M, Kfoury A, Kim D, Kobashigawa J, Shullo M, Stehlik J, Teuteberg J, Uber P, Zuckermann A, Hunt S, Burch M, Bhat G, Canter C, Chinnock R, Crespo-Leiro M, Delgado R, Dobbels F, Grady K, Kao W, Lamour J, Parry G, Patel J, Pini D, Towbin J, Wolfel G, Delgado D, Eisen H, Goldberg L, Hosenpud J, Johnson M, Keogh A, Lewis C, O’Connell J, Rogers J, Ross H, Russell S, Vanhaecke J; International Society of Heart and Lung Transplantation Guidelines. The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010;29:914–956. doi: 10.1016/j.healun.2010.05.034.
153. Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM, Chia D, Terasaki PI, Sabad A, Cogert GA, Trosian K, Hamilton MA, Moriguchi JD, Kawata N,Hage A, Drinkwater DC, Stevenson LW. Effect of pravastatin on outcomes after
cardiac transplantation. N Engl J Med. 1995;333:621–627. doi: 10.1056/NEJM199509073331003.
154. Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K, Steinbeck G, Seidel D, Reichart B. Simvastatin initiated early after heart transplantation: 8-year prospective experience. Circulation. 2003;107:93–97.
155. Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Steinbeck G, Seidel D, Reichart B. Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial. Circulation. 1997;96:1398–1402.
156. Lindenfeld J, Page RL 2nd, Zolty R, Shakar SF, Levi M, Lowes B, Wolfel EE, Miller GG. Drug therapy in the heart transplant recipient, part III: common medical problems. Circulation. 2005;111:113–117. doi: 10.1161/01.CIR.0000151609.60618.3C.
157. Zakliczynski M, Boguslawska J, Wojniak E, Zakliczynska H, Ciesla D, Nozynski J, Szygula-Jurkiewicz B, Zeglen S, Zembala M. In the era of the universal use of statins dyslipidemia’s are still common in heart transplant recipients: a cross-sectional study. Transplant Proc. 2011;43:3071–3073. doi: 10.1016/j.transproceed.2011.08.052.
158. Page RL 2nd, Miller GG, Lindenfeld J. Drug therapy in the heart transplant recipient, part IV: drug-drug interac-tions. Circulation. 2005;111:230–239. doi: 10.1161/01.CIR.0000151805.86933.35.
159. Campana C, Regazzi MB, Buggia I, Molinaro M. Clinically sig-nificant drug interactions with cyclosporine: an update. Clin Pharmacokinet. 1996;30:141–179.
160. Venkataramanan R, Swaminathan A, Prasad T, Jain A, Zuckerman S, Warty V, McMichael J, Lever J, Burckart G, Starzl T. Clinical phar-macokinetics of tacrolimus. Clin Pharmacokinet. 1995;29:404–430. doi: 10.2165/00003088-199529060-00003.
161. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80:565–581. doi: 10.1016/j.clpt.2006.09.003.
162. Ballantyne CM, Corsini A, Davidson MH, Holdaas H, Jacobson TA, Leitersdorf E, März W, Reckless JP, Stein EA. Risk for my-opathy with statin therapy in high-risk patients. Arch Intern Med. 2003;163:553–564.
164. Lemahieu WP, Hermann M, Asberg A, Verbeke K, Holdaas H, Vanrenterghem Y, Maes BD. Combined therapy with atorv-astatin and calcineurin inhibitors: no interactions with tacroli-mus. Am J Transplant. 2005;5:2236–2243. doi: 10.1111/ j.1600-6143.2005.01005.x.
165. Aliabadi AZ, Mahr S, Dunkler D, Grömmer M, Zimpfer D, Wolner E, Grimm M, Zuckermann AO. Safety and efficacy of statin ther-apy in patients switched from cyclosporine a to sirolimus after cardiac transplantation. Transplantation. 2008;86:1771–1776. doi: 10.1097/TP.0b013e3181910eb2.
166. Basic-Jukic N, Kes P, Bubic-Filipi L, Vranjican Z. Rhabdomyolysis and acute kidney injury secondary to concomitant use of fluvastatin and rapamycin in a renal transplant recipient. Nephrol Dial Transplant. 2010;25:2036; author reply 2036–2037. doi: 10.1093/ ndt/gfq157.
167. Dopazo C, Bilbao I, Lázaro JL, Sapisochin G, Caralt M, Blanco L, Castells L, Charco R. Severe rhabdomyolysis and acute renal failure secondary to concomitant use of simvastatin with rapamycin plus tacrolimus in liver transplant patient. Transplant Proc. 2009;41: 1021–1024. doi: 10.1016/j.transproceed.2009.02.019.
168. Kovarik JM, Hartmann S, Hubert M, Berthier S, Schneider W, Rosenkranz B, Rordorf C. Pharmacokinetic and pharmacody-namic assessments of HMG-CoA reductase inhibitors when coadministered with everolimus. J Clin Pharmacol. 2002;42: 222–228.
169. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013;61:404–410. doi: 10.1016/j.jacc.2012.10.027.
170. Baker SK, Goodwin S, Sur M, Tarnopolsky MA. Cytoskeletal myotoxicity from simvastatin and colchicine. Muscle Nerve. 2004;30:799–802. doi: 10.1002/mus.20135.
171. Tufan A, Dede DS, Cavus S, Altintas ND, Iskit AB, Topeli A. Rhabdomyolysis in a patient treated with colchicine and atorvas-tatin. Ann Pharmacother. 2006;40:1466–1469. doi: 10.1345/aph.1H064.
172. Sahin G, Korkmaz C, Yalcin AU. Which statin should be used to-gether with colchicine? Clinical experience in three patients with nephrotic syndrome due to AA type amyloidosis. Rheumatol Int. 2008;28:289–291. doi: 10.1007/s00296-007-0435-1.
173. Montiel V, Huberlant V, Vincent MF, Bonbled F, Hantson P. Multiple organ failure after an overdose of less than 0.4 mg/kg of colchicine: role of coingestants and drugs during intensive care management. Clin Toxicol (Phila). 2010;48:845–848. doi: 10.3109/15563650.2010.509101.
174. Atasoyu EM, Evrenkaya TR, Solmazgul E. Possible colchicine rhab-domyolysis in a fluvastatin-treated patient. Ann Pharmacother. 2005;39:1368–1369. doi: 10.1345/aph.1E653.
175. Sarullo FM, Americo L, Di Franco A, Di Pasquale P. Rhabdomyolysis induced by co-administration of fluvastatin and colchicine. Monaldi Arch Chest Dis. 2010;74:147–149. doi: 10.4081/monaldi.2010.264.
176. Torgovnick J, Sethi N, Arsura E. Colchicine and HMG Co-A reduc-tase inhibitors induced myopathy: a case report. Neurotoxicology. 2006;27:1126–1127. doi: 10.1016/j.neuro.2006.09.003.
177. Alayli G, Cengiz K, Cantürk F, Durmuş D, Akyol Y, Menekşe EB. Acute myopathy in a patient with concomitant use of pravastatin and colchicine. Ann Pharmacother. 2005;39:1358–1361. doi: 10.1345/aph.1E593.
178. Bouquié R, Deslandes G, Renaud C, Dailly E, Haloun A, Jolliet P. Colchicine-induced rhabdomyolysis in a heart/lung transplant patient with concurrent use of cyclosporin, pravastatin, and azithromycin. J Clin Rheumatol. 2011;17:28–30. doi: 10.1097/RHU.0b013e3182056042.
179. Hsu WC, Chen WH, Chang MT, Chiu HC. Colchicine-induced acute myopathy in a patient with concomitant use of simvastatin. Clin Neuropharmacol. 2002;25:266–268.
180. Francis L, Bonilla E, Soforo E, Neupane H, Nakhla H, Fuller C, Perl A. Fatal toxic myopathy attributed to propofol, methylpred-nisolone, and cyclosporine after prior exposure to colchicine and simvastatin. Clin Rheumatol. 2008;27:129–131. doi: 10.1007/s10067-007-0696-9.
181. Justiniano M, Dold S, Espinoza LR. Rapid onset of muscle weak-ness (rhabdomyolysis) associated with the combined use of sim-vastatin and colchicine. J Clin Rheumatol. 2007;13:266–268. doi: 10.1097/RHU.0b013e318156d977.
182. Oh DH, Chan SQ, Wilson AM. Myopathy and possible intestinal dysfunction in a patient treated with colchicine and simvastatin. Med J Aust. 2012;197:332–333.
183. Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised pla-cebo-controlled study [published correction appears in Lancet. 2010;376:1988]. Lancet. 2010;376:875–885. doi: 10.1016/S0140-6736(10)61198-1.
185. European Medicines Agent. Summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000597/WC500043590.pdf. Accessed April 21, 2016.
186. Sacubratril/Valsartan, Entresto [package insert]. East Hanover, NJ: Novartis; 2015.
187. European Medicines Agency. Assessment report: Entresto. 2015. http://www.ema.europa.eu/docs/en_GB/document_library/ EPAR_ -_Pub l ic_assessment_repor t/human/004062/WC500197538.pdf. Accessed April 21, 2016.
188. US Food and Drug Administration. Center for Drug Evaluation and Research: application number 207620Orig1s000: clinical pharmacology and biopharmaceutics review(s). http://www. accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf. Accessed April 21, 2016.
189. http://www.hiv-druginteractions.org/. Accessed August 28, 2016.
Functional Genomics and Translational Biologyon Hypertension; Council on Quality of Care and Outcomes Research; and Council on
Association Clinical Pharmacology Committee of the Council on Clinical Cardiology; CouncilKostis, David Lanfear, Salim Virani, Pamela B. Morris and On behalf of the American Heart
Barbara S. Wiggins, Joseph J. Saseen, Robert L. Page II, Brent N. Reed, Kevin Sneed, John B.Statement From the American Heart Association
Statins and Select Agents Used in Patients With Cardiovascular Disease: A Scientific Recommendations for Management of Clinically Significant Drug-Drug Interactions With
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation published online October 17, 2016;Circulation.
http://circ.ahajournals.org/content/early/2016/10/17/CIR.0000000000000456.citationWorld Wide Web at:
The online version of this article, along with updated information and services, is located on the
http://circ.ahajournals.org//subscriptions/
is online at: Circulation Information about subscribing to Subscriptions:
http://www.lww.com/reprints Information about reprints can be found online at: Reprints:
document. Permissions and Rights Question and Answer this process is available in the
click Request Permissions in the middle column of the Web page under Services. Further information aboutOffice. Once the online version of the published article for which permission is being requested is located,
can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialCirculationin Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions:
![HIGHLIGHTS OF PRESCRIBING INFORMATION ...saigaiin.sakura.ne.jp/sblo_files/saigaiin/image/zepatier_pi.pdf · Precautions (5.3), Drug Interactions (7),and Clinical Pharmacology (12.3)].](https://static.documents.pub/doc/80x56/61197a9fa474fc68a009b7ce/highlights-of-prescribing-information-precautions-53-drug-interactions-7and.jpg)
